TABLE 20.11: Contrasting Features of Non-neoplastic and Neoplastic Colorectal Polyps. 585
Feature Non-neoplastic polyps Neoplastic polyps (Adenomas)
1. Frequency More common Less common
2. Number Often sporadic Sporadic as well as multiple
3. Familial predisposition No Yes, in sporadic cases
4. Types Hyperplastic (90%) Tubular, villous and tubulovillous
Others: hamartomatous (Peutz-Jeghers, juvenile) adenomas
inflammatory, lymphoid
5. Familial syndromes Juvenile polyposis syndrome Familial polyposis coli, Gardner’s,
Turcot’s
6. Biologic behaviour Always benign Variable malignant potential:
Tubular adenoma 5%, villous 30%,
tubulovillous intermediate
known by other names like papillary adenoma and villo- Grossly and microscopically, the commonest pattern is
glandular adenoma. The distribution of these adenomas is that of adenomatous polyps (tubular adenomas)
the same as for tubular adenomas. discussed above.
Grossly, tubulovillous adenomas may be sessile or The malignant potential of familial polyposis coli is very
pedunculated and range in size from 0.5-5 cm. high. Colorectal cancer develops virtually in 100% of cases
Microscopically, they show intermediate or mixed by age of 50 years if not treated with colectomy. This subject
pattern, characteristic vertical villi and deeper part of ‘adenoma-carcinoma sequence’ has been discussed again
showing tubular pattern (Fig. 20.43,C).
on page 586.
The behaviour of tubulovillous adenoma is intermediate CHAPTER 20
between tubular and villous adenomas. Gardner’s Syndrome
The contrasting features of non-neoplastic and neoplastic Gardner’s syndrome is combination of familial polyposis coli
colorectal polyps are given in Table 20.11. and certain extra-colonic lesions such as multiple osteomas
(particularly of the mandible and maxilla), sebaceous cysts
C. FAMILIAL POLYPOSIS SYNDROMES
Familial polyposis syndromes are a group of disorders with
multiple polyposis of the colon with autosomal dominant
inheritance pattern. Important conditions included in familial
polyposis are:
1. Familial polyposis coli (adenomatosis)
2. Gardner’s syndrome The Gastrointestinal Tract
3. Turcot’s syndrome
4. Juvenile polyposis syndrome
Some other conditions in which multiple polyposis of
colon occur but do not have familial basis are Peutz-Jeghers
syndrome (hamartomatous), Cronkhite-Canada syndrome
(inflammatory), and nodular lymphoid hyperplasia. The
familial polyposis syndromes are as follows.
Familial Polyposis Coli (Adenomatosis)
This hereditary disease is defined as the presence of more
than 100 neoplastic polyps (adenomas) on the mucosal
surface of the colon; the average number is about 1000
(Fig. 20.44). Adenomatosis can be distinguished from
multiple adenomas in which the number of adenomas is
fewer, not exceeding 100. The condition has autosomal
dominant transmission and is due to germline mutations in
APC gene which results in occurrence of hundreds of
adenomas which progress to invasive cancer. The average Figure 20.44 Familial polyposis coli. The mucosal surface is
age at diagnosis is 2nd and 3rd decades of life with equal straddled with multiple polyoid structures (arrow) of varying sizes many
incidence in both the sexes. of which are pedunculated.
586 and connective tissue tumours. The number of polyps in duration changes the bacterial flora of the bowel, thus
Gardner’s syndrome is generally fewer than in the familial resulting in production of carcinogenic substances.
polyposis coli but their clinical behaviour is identical. 3. Adenoma-carcinoma sequence. There is strong evidence
to suggest that colonic adenocarcinoma evolves from pre-
Turcot’s Syndrome existing adenomas, referred to as adenoma-carcinoma
Turcot’s syndrome is combination of familial polyposis coli sequence (Fig. 20.45). The following evidences are cited to
and malignant neoplasms of the central nervous system. support this hypothesis:
i) In a case with early invasive cancer, the surrounding
Juvenile Polyposis Syndrome tissue often shows preceding changes of evolution from
adenoma → hyperplasia → dysplasia → carcinoma in situ →
Juvenile polyposis is appearance of multiple juvenile polyps invasive carcinoma.
in the colon, stomach and small intestine but their number is ii) Incidence of adenomas in a population is directly propor-
not as high as in familial polyposis coli. Family history in tionate to the prevalence of colorectal cancer.
some cases may show autosomal dominant inheritance iii) The risk of adenocarcinoma colon declines with endoscopic
pattern, while it may be negative in others. They resemble removal of all identified adenomas.
the typical juvenile polyps as regards their age (under 5 iv) Peak incidence of adenomas generally precedes by some
years), sex distribution and morphology. They lack the years to a few decades the peak incidence for colorectal
malignant potential. cancer.
v) The risk of malignancy increases with the following
OTHER BENIGN TUMOURS adenoma-related factors:
Some non-epithelial benign tumours that may rarely occur a) Number of adenomas: familial polyposis coli syndrome
in large intestine are leiomyomas, leiomyoblastoma, neuri- almost certainly evolves into malignancy.
lemmoma, lipoma and vascular tumours (haemangioma, b) Size of adenomas: large size increases the risk.
lymphangioma). c) Type of adenomas: greater villous component associated
with higher prevalence.
MALIGNANT COLORECTAL TUMOURS 4. Hereditary non-polyposis colonic cancer (HNPCC or
Lynch syndrome). HNPCC is an autosomal dominant
A. Colorectal Carcinoma condition in which colorectal cancer is seen in at least two
SECTION III
Colorectal cancer comprises 98% of all malignant tumours generations of first-degree relatives before the age of 50 years,
of the large intestine. It is the commonest form of visceral without evidence of familial polyposis coli. There are germline
cancer accounting for deaths from cancer in the United States, mutations in mismatch repair genes, human mutL homolog
next only to lung cancer. The incidence of carcinoma of the abbreviated as hMLH2 located on chromosome 2 and hMLH1
large intestine rises with age; average age of patients is about on chromosome 3 resulting in DNA instability. In HNPCC,
60 years. Cancer in the rectum is more common in males colon cancer appears at a relatively younger age (<50 years),
than females in the ratio of 2:1, while at other locations in association with multiple primary cancers at different sites
the large bowel the overall incidence is equal for both sexes. (e.g. endometrium, ovary), preferred location in proximal
colon and better prognosis than other sporadic colon cancer
ETIOLOGY. As with most other cancers, etiology of cases.
colorectal carcinoma is not clear but a few etiological factors 5. Other factors. Presence of certain pre-existing diseases
have been implicated:
Systemic Pathology
such as inflammatory bowel disease (especially ulcerative
1. Geographic variations. The incidence of large bowel colitis) and diverticular disease for long duration increase
carcinoma shows wide variation throughout the world. It is the risk of developing colorectal cancer subsequently. It may
much more common in North America, Northern Europe be recalled here that low fibre diet is implicated in the
than in South America, Africa and Asia. Colorectal cancer is pathogenesis of diverticular disease as well. Besides, there
generally thought to be a disease of affluent societies because is an etiologic role of tobacco smoking in development of
its incidence is directly correlated with the socioeconomic colorectal cancer in youger patients.
status of the countries. In Japan, however, colon cancer is
much less common than in the US but the incidence of rectal GENETIC BASIS OF COLORECTAL CARCINOGENESIS.
cancer is similar. Studies by molecular genetics have revealed that there are
2. Dietary factors. Diet plays a significant part in the sequential multistep mutations in evolution of colorectal
causation of colorectal cancer: cancer from adenomas by one of the following two
i) A low intake of vegetable fibre-diet leading to low stool mechanisms:
bulk is associated with higher risk of colorectal cancer. 1. APC mutation/ β β β β β-catenin mechanism. This pathway of
ii) Consumption of large amounts of fatty foods by multiple mutations is generally associated with
populations results in excessive cholesterol and their morphologically identifiable changes as described above in
metabolites which may be carcinogenic. adenoma-carcinoma sequence. These changes are as under:
iii) Excessive consumption of refined carbohydrates that i) Loss of tumour suppressor APC (adenomatous polyposis coli)
remain in contact with the colonic mucosa for prolonged gene located on the long arm of chromosome 5 (5q) is present
587
Figure 20.45 Adenoma-carcinoma sequence—schematic diagram of molecular and morphologic evolution. CHAPTER 20
in 80% cases of sporadic colon cancer. Since the function of MORPHOLOGIC FEATURES. Distribution of the primary
APC gene is linked to β-catenin, loss of APC gene results in colorectal cancer reveals that about 60% of the cases occur
translocation of β-catenin to the nucleus where it activates in the rectum, followed in descending order, by sigmoid
transcription of other genes, mainly MYC and cyclin D1, both and descending colon (25%), caecum and ileocaecal valve
of which stimulate cell proliferation. (10%); ascending colon, hepatic and splenic flexures (5%);
ii) Point mutation in K-RAS gene follows loss of APC gene and quite uncommonly in the transverse colon (Fig. 20.46).
and is seen in 10 to 50% cases of adenoma-carcinoma. The Gastrointestinal Tract
iii) Deletion of DCC gene located on long arm of chromosome Grossly, there are distinct differences between the growth
18 i.e. 18q (DCC for deleted in colorectal cancer) in 60-70% on the right and left half of the colon (Fig. 20.47).
cases of colon cancer.
iv) Loss of p53 tumour suppressor gene seen in 70-80% cases of
colon cancer.
2. Microsatellite instability mechanism. In this pathway
also, there are multiple mutations but of different genes,
and unlike APC mutation/β-catenin mechanism there are
no morphologically identifiable changes. This pathway
accounts for 10-15% cases of colon cancer. Basic mutation
is loss of DNA repair gene. This results in a situation in
which repetitive DNA sequences (i.e. microsatellites)
become unstable during replication cycle, termed
microsatellite instability, which is the hallmark of this
pathway. The significant DNA repair genes which are
mutated in colon cancer are as under:
i) TGF-β receptor gene which normally inhibits cell
proliferation but in mutated form allows the uncontrolled
proliferation of colonic epithelium in adenoma.
ii) BAX gene which normally causes apoptosis but a defect in
it results in loss of apoptosis and dysregulated growth. Figure 20.46 Distribution of the primary colorectal cancer.
588
SECTION III
Figure 20.47 Gross appearance of colorectal carcinoma. A, Right-sided growth—fungating polypoid carcinoma showing cauliflower-like growth
projecting into the lumen. B, Left-sided growth—napkin-ring configuration with spread of growth into the bowel wall.
Systemic Pathology
Right-sided colonic growths tend to be large, cauli- Microscopically, the appearance of right and left-sided
flower-like, soft and friable masses projecting into the growths is similar. About 95% of colorectal carcinomas
lumen (fungating polypoid carcinoma). are adenocarcinomas of varying grades of differentiation,
Left-sided colonic growths, on the other hand, have out of which approximately 10% are mucin-secreting
napkin-ring configuration i.e. they encircle the bowel wall colloid carcinomas (Fig. 20.48). The remaining 5% tumours
circumferentially with increased fibrous tissue forming include uncommon microscopic patterns like undifferen-
annular ring, and have central ulceration on the surface tiated carcinoma, signet-ring cell carcinoma, and adeno-
with slightly elevated margins (carcinomatous ulcers). squamous carcinomas seen in more distal colon near the
These differences in right and left colonic growths are anus. The histologic grades indicating the degree of
probably due to the liquid nature of the contents in the differentiation are: well-differentiated, moderately-
ascending colon leaving space for luminal growth on right differentiated and poorly-differentiated.
side, while the contents in left colon are more solid SPREAD. Carcinoma of the large intestine may spread by
permitting the spread of growth into the bowel wall. the following routes:
However, early lesion in left as well as right colon are
small, button-like areas of elevation. 1. Direct spread. The tumour spreads most commonly by
direct extension in both ways— circumferentially into the
589
Figure 20.48 Colonic adenocarcinoma. A, Moderately differentiated. B, Mucin-secreting adenocarcinoma.
bowel wall as well as directly into the depth of the bowel STAGING AND PROGNOSIS. The prognosis of colorectal
wall to the serosa, pericolic fat, and sometimes into peritoneal cancer depends upon a few variables:
cavity. i) Extent of the bowel involvement
2. Lymphatic spread. Spread via lymphatics occurs rather ii) Presence or absence of metastases
commonly and involves, firstly the regional lymph nodes in iii) Histologic grade of the tumour CHAPTER 20
the vicinity of the tumour, and then into other groups of iv) Location of the tumour
lymph nodes like preaortic, internal iliac and the sacral lymph The most important prognostic factor in colorectal cancer
nodes. is, however, the stage of the disease at the time of diagnosis.
Three staging systems are in use:
3. Haematogenous spread. Blood spread of large bowel 1. Dukes’ ABC staging (modified Duke’s includes stage D as
cancer occurs relatively late and involves the liver, lungs, well).
brain, bones and ovary.
2. Astler-Coller staging which is a further modification of
CLINICAL FEATURES. Clinical symptoms in colorectal Duke’s staging and is most widely used.
cancer appear after considerable time. These are as follows: 3. TNM staging described by American Joint Committee is
i) Occult bleeding (melaena) also used.
ii) Change in bowel habits, more often in left-sided growth Table 20.12 and Fig. 20.49 sum up the features of staging The Gastrointestinal Tract
iii) Loss of weight (cachexia) classification and the overall 5-year survival rate in disease
iv) Loss of appetite (anorexia) stage.
v) Anaemia, weakness, malaise.
The most common complications are obstruction and B. Other Colorectal Malignant Tumours
haemorrhage; less often perforation and secondary infection Aside from colorectal carcinoma, other malignant tumours
may occur. Aside from the diagnostic methods like stool test which are encountered sometimes in the large bowel are
for occult blood, PR examination, proctoscopy, radiographic leiomyosarcoma (page 737) and malignant lymphoma (page
contrast studies and CT scan, recently the role of tumour- 559). Hindgut carcinoids may occur in the rectum and colon
markers has been emphasised. Of particular importance is (page 576).
the estimation of carcinoembryonic antigen (CEA) level
which is elevated in 100% cases of metastatic colorectal TUMOURS OF THE ANAL CANAL
cancers, while it is positive in 20-40% of early lesions, and
60-70% of advanced primary lesions. However, the test may Epithelial tumours of the anal canal are uncommon and may
have prognostic significance only and is not diagnostic of be combination of several histological types. Amongst the
colorectal cancer because it is positive in other cancers too benign tumours of the anal canal, multiple viral warts called
such as of the lungs, breast, ovary, urinary bladder and as condyloma acuminata are the only tumours of note.
prostate. CEA levels are elevated in some non-neoplastic Malignant tumours of the anal canal include the following:
conditions also like in ulcerative colitis, pancreatitis and 1. Squamous cell carcinoma (Fig. 20.50)
alcoholic cirrhosis. 2. Basaloid carcinoma
590
Figure 20.49 Pathologic staging according to Astler-Coller system. (Also see facing Table 20.12).
3. Mucoepidermoid carcinoma presenting clinical feature of a variety of gastrointestinal
4. Adenocarcinoma (rectal, of anal glands, within anorectal diseases. Table 20.13 summarises the main causes of
fistulas) gastrointestinal bleeding.
5. Undifferentiated carcinoma
6. Malignant melanoma.
These tumours resemble in morphology with similar PERITONEUM
lesion elsewhere in the body.
NORMAL STRUCTURE
CAUSES OF GASTROINTESTINAL BLEEDING The peritoneal cavity is lined by a layer of surface meso-
Gastrointestinal bleeding from upper (haematemesis), thelium derived from mesoderm. The lining rests on
middle (small intestinal) and lower (melaena) is a major vascularised subserosal fibrous tissue. Other structures
topographically related to peritoneum are retroperitoneum,
omentum, mesentery and umbilicus. These structures are
SECTION III
involved in a variety of pathologic states but a few important
conditions included below are inflammation (peritonitis),
tumour-like lesions (idiopathic retroperitoneal fibrosis and
mesenteric cysts) and tumours (primary and metastatic).
PERITONITIS
Inflammatory involvement of the peritoneum may result
from chemical agents or bacteria.
1. Chemical peritonitis can be caused by the following:
Bile extravasated due to trauma or diseases of the
Systemic Pathology
gallbladder.
Pancreatic secretions released from pancreas in acute
haemorrhagic pancreatitis.
Gastric juice leaked from perforation of stomach.
Barium sulfate from perforation of bowel during
radiographic studies.
Chemical peritonitis is localised or generalised sterile
inflammation of the peritoneum.
2. Bacterial peritonitis may be primary or secondary; the
latter being more common.
Primary form is caused by streptococcal infection,
especially in children. Secondary bacterial peritonitis may
occur from the following disorders:
Appendicitis
Figure 20.50 Anorectal carcinoma. The anorectal margin shows Cholecystitis
an ulcerated mucosa with thickened wall (arrow). The sectioned surface
of rectal wall is grey-white and fleshy due to infiltration by the tumour. Salpingitis
591
TABLE 20.12: Staging and Prognosis of Colorectal Cancer (Duke's System as Modified by Astler-Coller).
Stage TNM 5-year Survival Pathologic Features
A I T 1 No Mo >90% Cancer confined to mucosa only
B 1 II T No Mo 85% Cancer extends into submucosa
2
B 2 II T No Mo 70-80% Cancer extends into muscularis+serosa
3
III Tx N 1 Mo 35-65% Cancer involves muscularis+regional lymph nodes
C 1
III Tx N 1 Mo 20-35% Cancer extends into serosa+regional lymph nodes
C 2
D IV Tx Nx M 1 5% Cancer with distant metastases
Rupture of peptic ulcer MESENTERIC CYSTS
Gangrene of bowel
Mesenteric cysts of unknown etiology and varying sizes may
Tuberculosis (specific inflammation). be found in the peritoneal cavity. On the basis of their
possible origin, they are of various types:
MORPHOLOGIC FEATURES Depending upon duration, Chylous cyst is a thin-walled cyst arising from lymph
the features in bacterial peritonitis vary. It may be vessels and lined by endothelium.
generalised or may get localised by omentum such as in Pseudocysts are those which are formed following walled-
appendiceal abscess following acute appendicitis. Depen- off infection or pancreatitis.
ding upon duration, the fluid accumulation varies from Neoplastic cysts occur due to cystic change in tumours.
serous, turbid, creamy to frankly suppurative. The fluid
may eventually resolve or may heal by organisation with TUMOURS
formation of fibrous adhesions. Peritoneum may be involved in malignant tumours—
primary and metastatic.
IDIOPATHIC RETROPERITONEAL FIBROSIS Mesothelioma is an example of primary peritoneal CHAPTER 20
tumour (benign and malignant) and is similar in morphology
Also known as Ormond’s disease or sclerosing retro- as in pleural cavity (page 505).
peritonitis, this rare entity of unknown etiology is characteri- Intra-abdominal desmoplastic small cell tumour is a
sed by diffuse fibrous overgrowth and chronic inflammation. recently described highly malignant tumour belonging to the
The condition is, therefore, more like inflammatory rather group of other round cell or blue cell tumours such as small
than neoplastic in origin. It may be associated with similar cell carcinoma lung, Ewing’s sarcoma, rhabdomyosarcoma,
process in the mediastinum, sclerosing cholangitis and neuroblastoma and others.
Riedel’s thyroiditis and termed multifocal fibrosclerosis. Metastatic peritoneal tumours are quite common and
Though idiopathic, the etiologic role of ergot derivative drugs may occur from dissemination from any intra-abdominal
and autoimmune reaction has been suggested. malignancy. The Gastrointestinal Tract
TABLE 20.13: Causes of Gastrointestinal (G.I.) Bleeding.
Upper G.I. Bleeding Small Intestinal Bleeding Lower G.I. Bleeding
1. Oesophageal varices Vascular ectasias Inflammatory bowel disease (IBD)
2. Mallory-Weiss tear Tumours (adenocarcinoma, lymphoma, leiomyoma) Carcinoma colon
3. Haemorrhagic/erosive gastritis NSAIDs Carcinoma rectosigmoid
4. Duodenal ulcer Meckel's diverticulum Haemorrhoids
5. Gastric ulcer Intussusception Anal fissure
6. Cancer stomach Crohn's disease Diverticulosis
❑
592
The Liver, Biliary Tract and
Chapter 21
Chapter 21
Exocrine Pancreas
LIVER
NORMAL STRUCTURE
ANATOMY. The liver is the largest organ in the body
weighing 1400-1600 gm in the males and 1200-1400 gm in
the females. There are 2 main anatomical lobes—right and
left, the right being about six times the size of the left lobe.
The right lobe has quadrate lobe on its inferior surface and a
caudate lobe on the posterior surface. The right and left lobes
are separated anteriorly by a fold of peritoneum called the
falciform ligament, inferiorly by the fissure for the ligamentum
teres, and posteriorly by the fissure for the ligamentum
venosum (Fig. 21.1).
The porta hepatis is the region on the inferior surface of
the right lobe where blood vessels, lymphatics and common
hepatic duct form the hilum of the liver. A firm smooth layer
of connective tissue called Glisson’s capsule encloses the liver Figure 21.2 Histology of hepatic lobule. The hexagonal or pyramidal
and is continuous with the connective tissue of the porta structure with central vein and peripheral 4 to 5 portal triads is termed
the classical lobule. The functional divisions of the lobule into 3 zones
SECTION III
hepatis forming a sheath around the structures in the porta are shown by circles.
hepatis. The liver has a double blood supply—the portal vein
brings the venous blood from the intestines and spleen, and join in the porta to form the common hepatic duct. The
the hepatic artery coming from the coeliac axis supplies venous drainage from the liver is into the right and left
arterial blood to the liver. This dual blood supply provides hepatic veins which enter the inferior vena cava. Lymphatics
sufficient protection against infarction in the liver. The portal and the nerve fibres accompany the hepatic artery into their
vein and hepatic artery divide into branches to the right and branchings and terminate around the porta hepatis.
left lobes in the porta. The right and left hepatic ducts also
HISTOLOGY. The hepatic parenchyma is composed of
numerous hexagonal or pyramidal classical lobules, each with
a diameter of 0.5 to 2 mm. Each classical lobule has a central
tributary from the hepatic vein and at the periphery are 4 to
Systemic Pathology
5 portal tracts or triads containing branches of bile duct,
portal vein and hepatic artery. Cords of hepatocytes and
blood-containing sinusoids radiate from the central vein to
the peripheral portal triads. The functioning lobule or liver
acinus as described by Rappaport has a portal triad in the
centre and is surrounded at the periphery by portions of
several classical lobules. However, in most descriptions on
pathology of the liver, the term lobule is used in its classical
form.
The blood supply to the liver parenchyma flows from
the portal triads to the central veins. Accordingly, the hepatic
parenchyma of liver lobule is divided into 3 zones (Fig. 21.2):
Zone 1 or the periportal (peripheral) area is closest to the
arterial and portal blood supply and hence bears the brunt
of all forms of toxic injury.
Zone 3 or the centrilobular area surrounds the central vein
and is most remote from the blood supply and thus suffers
from the effects of hypoxic injury.
Figure 21.1 Anatomy of the liver and its relationship to the
gallbladder, pancreas and duodenum. Zone 2 is the intermediate midzonal area.
The hepatocytes are polygonal cells with a round single synthesis and elimination of bilirubin pigment, urobilino- 593
nucleus and a prominent nucleolus. The liver cells have a gen and bile acids are as follows:
remarkable capability to undergo mitosis and regeneration. 1. BILIRUBIN. Bilirubin pigment can be detected in serum,
Thus it is not uncommon to find liver cells containing more faeces and urine.
than one nuclei and having polyploidy up to octoploidy. A
hepatocyte has 3 surfaces: one facing the sinusoid and the i) Serum bilirubin estimation is based on van den Bergh
space of Disse, the second facing the canaliculus, and the third diazo reaction by spectrophotometric method. Diazo reagent
facing neighbouring hepatocytes. consists of diazotised sulfanilic acid. Water-soluble conjugated
The blood-containing sinusoids between cords of hepato- bilirubin gives direct van den Bergh reaction with diazo
cytes are lined by discontinuous endothelial cells and scatte- reagent within one minute, whereas alcohol-soluble
red flat Kupffer cells belonging to the reticuloendothelial unconjugated bilirubin is determined by indirect van den
system. Bergh reaction. Addition of alcohol to the reaction mixture
The space of Disse is the space between hepatocytes and gives positive test for both conjugated and unconjugated
sinusoidal lining endothelial cells. A few scattered fat storing bilirubin pigment. The unconjugated bilirubin level is then
Ito cells lie within the space of Disse. estimated by subtracting direct bilirubin value from this total
The portal triad or tract besides containing portal vein value. The serum of normal adults contains less than 1 mg/
radicle, the hepatic arteriole and bile duct, has a few dl of total bilirubin, out of which less than 0.25 mg/dl is
mononuclear cells and a scanty connective tissue considered conjugated bilirubin. Bilirubin level rises in diseases of
to be extension of Glisson’s capsule. The portal triads are hepatocytes, obstruction to biliary excretion into the
surrounded by a limiting plate of hepatocytes. duodenum, in haemolysis, and defects of hepatic uptake and
The intrahepatic biliary system begins with the bile conjugation of bilirubin pigment such as in Gilbert’s disease.
canaliculi interposed between the adjacent hepatocytes. The ii) In faeces, excretion of bilirubin is assessed by inspection
bile canaliculi are simply grooves between the contact of stools. Clay-coloured stool due to absence of faecal
surfaces of the liver cells and are covered by microvilli. These excretion of the pigment indicates obstructive jaundice.
canaliculi join at the periphery of the lobule to drain iii) In urine, conjugated bilirubin can be detected by
eventually into terminal bile ducts or ductules (canal of commercially available ‘dipsticks’, Fouchet’s test, foam test CHAPTER 21
Hering) which are lined by cuboidal epithelium. or ictotest tablet method. Bilirubinuria does not occur in
FUNCTIONS. The liver performs multifold functions. These normal subjects nor is unconjugated bilirubin excreted in the
are briefly listed below: urine. Bilirubinuria occurs only when there is raised level of
1. Manufacture and excretion of bile. conjugated bilirubin (filterable). Its excretion depends upon
2. Manufacture of several major plasma proteins such as the level of conjugated bilirubin in plasma that is not protein-
albumin, fibrinogen and prothrombin. bound and is therefore available for glomerular filtration.
3. Metabolism of proteins, carbohydrates and lipids. Bilirubinuria appears in patients of hepatitis before the
4. Storage of vitamins (A, D and B ) and iron. patient becomes jaundiced.
12
5. Detoxification of toxic substances such as alcohol and 2. UROBILINOGEN. Urobilinogen is normally excreted in
drugs. the urine. Its semiquantitative estimation in the urine can be
done by preparing dilutions with Ehrlich’s aldehyde reagent
LIVER FUNCTION TESTS or by ‘dipstick’ method. An increase in urobilinogen in the
In view of multiplicity and complexity of the liver functions, urine is found in hepatocellular dysfunctions such as in
it is obvious that no single test can establish the disturbance alcoholic liver disease, cirrhosis and malignancy of the liver.
in liver function. Thus a battery of liver function tests are It is also raised in haemolytic disease and in pyrexia. In The Liver, Biliary Tract and Exocrine Pancreas
employed for accurate diagnosis, to assess the severity of cholestatic jaundice due to complete biliary obstruction,
damage, to judge prognosis and to evaluate therapy. These urobilinogen disappears from the urine.
tests are described below in relation to major liver functions. 3. BROMSULPHALEIN EXCRETION. Bromsulphalein
A summary of various liver function tests is given in (BSP) is a dye which is removed from circulation by the same
Table 21.1. mechanisms of binding, conjugation and excretion as
bilirubin. BSP is injected intravenously and a sample of
I. TESTS FOR MANUFACTURE AND venous blood 45 minutes later is tested for percentage of
EXCRETION OF BILE injected dye remaining in the blood. The test is rarely
performed nowadays because of the availability of enzyme
Bile is produced by the liver, stored in the gallbladder and
secreted via biliary ducts into the duodenum. Bile consists estimations which are better indicators of hepatic
of biliary phospholipids and primary and secondary bile dysfunction. Presently, the only value of BSP excretion test
acids. To understand the mechanisms underlying biliary is in the diagnosis of Dubin-Johnson’s syndrome (page 601).
pathology, it is important to understand normal bilirubin 4. BILE ACIDS (BILE SALTS). The primary bile acids
metabolism (page 596). In brief, jaundice will develop if (cholic acid and cheno-deoxycholic acid) are formed from
bilirubin is excessively produced, or there is impaired hepatic cholesterol in the hepatocytes. These bile acids on secretion
uptake and conjugation of bilirubin, or it is insufficiently into the gut come in contact with colonic bacteria and
excreted into the duodenum. Tests employed to assess the undergo deconjugation with the production of secondary bile
594
TABLE 21.1: Liver Function Tests.
Tests Significance
I. TESTS FOR MANUFACTURE AND EXCRETION OF BILE
1. Bilirubin:
i) Serum bilirubin Increased in hepatocellular, obstructive and haemolytic disease,
Gilbert’s disease
ii) In faeces Absent in biliary obstruction
iii) In urine Conjugated bilirubinuria in patients of hepatitis
2. Urobilinogen: Increased in hepatocellular and haemolytic diseases, absent in
biliary obstruction
3. Bile acid (Bile salts): Increased in serum and detectable in urine in cholestasis
II. SERUM ENZYME ASSAYS
1. Alkaline phosphatase: Increased in hepatobiliary disease (highest in biliary obstruction),
bone diseases, pregnancy
2. γ-Glutamyl transpeptidase (γ-GT): Rise parallels alkaline phosphatase but is specific for hepatobiliary diseases
3. Transaminases:
i) SGOT (AST) Increased in tissue injury to liver as well as to other tissues like
in myocardial infarction
ii) SGPT (ALT) Increase is fairly specific for liver cell injury
4. Other enzymes:
i) 5'-Nucleotidase Rise parallels alkaline phosphatase but more specific for diseases of
hepatic origin
ii) Lactic dehydrogenase Increased in tumours involving the liver
iii) Cholinesterase Decreased in hepatocellular disease, malnutrition
III. TESTS FOR METABOLIC FUNCTIONS
1. Amino acid and protein metabolism:
i) Serum proteins (total, A/G ratio, Hypoalbuminaemia in hepatocellular diseases;
SECTION III
protein electrophoresis) hyperglobulinaemia in cirrhosis and chronic active hepatitis
ii) Immunoglobulins Nonspecific alterations in IgA, IgG and IgM
iii) Clotting factors Prothrombin time and partial thromboplastin time prolonged
in patients with hepatocellular disease
iv) Serum ammonia Increased in acute fulminant hepatitis, cirrhosis, hepatic encephalopathy
v) Aminoaciduria In fulminant hepatitis
2. Lipid and lipoprotein metabolism:
Blood lipids (total serum cholesterol, Increased in cholestasis, decreased in acute and chronic
triglycerides and lipoprotein fractions) diffuse liver disease and in malnutrition
3. Carbohydrate metabolism:
Blood glucose and GTT Decreased in hepatic necrosis
Systemic Pathology
IV. IMMUNOLOGIC TESTS
1. Nonspecific immunologic reactions:
i) Smooth muscle antibody In hepatic necrosis
ii) Mitochondrial antibody In primary biliary cirrhosis
iii) Antinuclear antibody and LE cell test In chronic active hepatitis
2. Antibodies to specific etiologic agents:
i) Antibodies to hepatitis B (HBsAg, HBc, HBeAg) In hepatitis B
ii) Amoeba antibodies Amoebic liver abscess
V. ANCILLARY DIAGNOSTIC TESTS
1. Ultrasound examination Cholestasis of various etiologies; SOLs, US-guided-FNAC/liver biopsy
2. FNAC and/ or percutaneous liver biopsy Unknown cause of hepatocellular disease, hepatomegaly and
splenomegaly; long-standing hepatitis; PUO and SOLs of the liver
acids (deoxycholic acid and lithocholic acid). Most of these Hepatobiliary diseases with cholestasis are associated
bile acids are reabsorbed through enterohepatic circulation with raised levels of serum bile acids which are responsible
and reach the liver. Only about 10% of the total bile acids for producing itching (pruritus). These acids are excreted in
are excreted in the faeces normally as unabsorbable toxic the urine by active transport and passive diffusion and can
lithocholic acid. be detected by simple methods as Hay’s test and ‘dipsticks’.
II. SERUM ENZYME ASSAYS i) 5'-Nucleotidase is another phosphatase derived from the 595
liver. Its determination is useful to distinguish alkaline
Determination of certain serum enzymes is considered useful phosphatase of hepatic origin from that of bony tissue.
in various types of liver injury, whether hepatocellular or
cholestatic, as well as in quantifying liver damage. A ii) Lactic dehydrogenase (LDH) is found to be elevated in
combination of serum transaminases and alkaline serum of patients with metastatic liver involvement.
phosphatase estimation is adequate to diagnose liver injury. iii) Choline esterase synthesised by the liver is diminished in
hepatocellular disease and malnutrition due to impaired
1. ALKALINE PHOSPHATASE. Serum alkaline phos- synthesis.
phatase is produced by many tissues, especially bone, liver,
intestine and placenta and is excreted in the bile. Most of the III. TESTS FOR METABOLIC FUNCTIONS
normal serum alkaline phosphatase (range 33-96 U/L) is
derived from bone. Elevation in activity of the enzyme can The liver is the principal site of metabolism and synthesis of
thus be found in diseases of bone, liver and in pregnancy. In plasma proteins and amino acids, lipids and lipoproteins,
the absence of bone disease and pregnancy, an elevated carbohydrates and vitamins, besides detoxification of drugs
serum alkaline phosphatase levels generally reflect and alcohol.
hepatobiliary disease. The greatest elevation (3 to 10 times 1. AMINO ACID AND PLASMA PROTEIN META-
normal) occurs in biliary tract obstruction. Slight to moderate BOLISM. Amino acids derived from the diet and from
increase is seen in parenchymal liver diseases such as in tissue breakdown are metabolised in the liver to ammonia
hepatitis and cirrhosis and in metastatic liver disease. It is and urea. A number of plasma proteins and immuno-
possible to distinguish serum hepatic alkaline phosphatase globulins are synthesised on polyribosomes bound to the
from bony alkaline phosphatase by fractionation into rough endoplasmic reticulum within the hepatocytes and
isoenzymes but this is not routinely done. discharged into plasma. Based on these metabolic functions
2. γγ γγ γ-GLUTAMYL TRANSPEPTIDASE (γγ γ γ γ-GT). The of the liver, serum estimation of proteins, immunoglobulins
primary source of the enzyme, γ-GT, in serum is the liver. and ammonia and aminoaciduria are employed to assess
Its serum level parallels serum alkaline phosphatase and is the liver cell damage.
used to confirm that the elevated serum alkaline phosphatase i) Serum proteins. Liver cells synthesise albumin, CHAPTER 21
is of hepatobiliary origin. Besides its elevation in cholestasis fibrinogen, prothrombin, alpha-1-antitrypsin, haptoglobin,
and hepatocellular disease, the levels are high in patients ceruloplasmin, transferrin, alpha fetoproteins and acute
with alcohol abuse even without liver disease. phase reactant proteins. The blood levels of these plasma
proteins are decreased in extensive liver damage. Routinely
3. TRANSAMINASES (AMINOTRANSFERASES). estimated are total concentration of serum proteins (normal
Assessment of liver cell necrosis is most frequently done by 6.7 to 8.6 gm/dl), serum albumin (normal 3.5 to 5.5 gm/dl),
estimation of the following 2 serum enzymes:
serum globulin (normal 2 to 3.5 gm/dl) and albumin/
i) Serum aspartate transaminase or AST (formerly globulin (A/G) ratio (normal 1.5-3:1). Electrophoresis is used
glutamic oxaloacetic transaminase or SGOT): AST or SGOT to determine the proportions of α , α , β and γ globulins.
2
1
is a mitochondrial enzyme released from heart, liver, skeletal Due to the availability of protein electrophoresis, thymol
muscle and kidney. Its normal serum level is 0.20-0.65 turbidity and flocculation tests based on altered plasma
μkat/L (12-38 U/L). protein components have been discontinued.
ii) Serum alanine transaminase or ALT (formerly glutamic Hypoalbuminaemia may occur in liver diseases having
pyruvic transaminase or SGPT): ALT or SGPT is a cytosolic significant destruction of hepatocytes. Hyperglobulinaemia
enzyme primarily present in the liver. Its normal serum level may be present in chronic inflammatory disorders such as The Liver, Biliary Tract and Exocrine Pancreas
is 0.12-0.70 μkat/L (7-41 U/L). in cirrhosis and chronic hepatitis.
Serum levels of SGOT and SGPT are increased on damage ii) Immunoglobulins. The levels of serum immuno-
to the tissues producing them. Thus serum estimation of globulins produced by lymphocytes and plasma cells (IgG,
SGPT (ALT) which is fairly specific for liver tissue is of IgM and IgA) show nonspecific abnormalities in liver
greater value in liver cell injury, whereas SGOT (AST) level diseases and represent inflammatory or immune response
may rise in acute necrosis or ischaemia of other organs such rather than liver cell dysfunction. IgA is the predominant
as the myocardium, besides liver cell injury. immunoglobulin in bile and its level is raised in cirrhosis,
Transaminase estimations are useful in the early IgG is markedly raised in chronic active hepatitis and IgM
diagnosis of viral hepatitis. Very high levels are seen in is markedly increased in primary biliary cirrhosis.
extensive acute hepatic necrosis such as in severe viral iii) Clotting factors. Hepatic synthetic function of several
hepatitis and acute cholestasis. Alcoholic liver disease and clotting factors can be assessed by a few simple coagulation
cirrhosis are associated with mild to moderate elevation of tests. Prothrombin time and partial thromboplastin time,
transaminases.
both of which reflect the activities of various clotting factors,
4. OTHER SERUM ENZYMES. The determination of a few are prolonged in patients with hepatocellular disease.
other serum enzymes is done sometimes but without any Prothrombin time is dependent upon both hepatic synthesis
extra diagnostic advantage over the above mentioned of clotting factors and intestinal uptake of vitamin K, a fat-
enzyme assays. These are as under: soluble vitamin. Thus, obstruction of the bile duct and intra-
596 hepatic cholestasis which result in vitamin K deficiency due iii) Hepatitis Be antigen (HBeAg) can be found in chronic
to impaired lipid absorption, are associated with prolonged varieties of hepatitis B.
prothrombin time. However, parenteral injection of vitamin iv) Amoeba antibodies to Entamoeba histolytica develop in
K will normalise prothrombin time if the prolongation was patients with amoebic liver abscess.
due to obstruction, but there will be no improvement in
prothrombin time if there is extensive hepatocellular disease. V. ANCILLARY DIAGNOSTIC TESTS
iv) Serum ammonia. High blood levels of ammonia are In addition to laboratory tests described above, two ancillary
found in acute fulminant hepatitis, cirrhosis and hepatic tests which are invariably done by the physician are
encephalopathy. The rise in serum ammonia is due to ultrasonography and percutaneous liver biopsy and/or
inability of severely damaged liver to convert ammonia to FNAC.
urea. Thus, urea synthesis is reduced in chronic liver disease.
1. ULTRASONOGRAPHY. Ultrasound (US) examination
2. LIPID AND LIPOPROTEIN METABOLISM. Lipids of the liver is indicated in the following situations:
synthesised in the liver include cholesterol and cholesterol i) Cholestasis of various etiologies to see the dilated intra-
esters, phospholipids and triglycerides. These lipids are and extrahepatic canalicular tree.
insoluble in water and are carried in circulation with three ii) Space-occupying lesions (SOLs) within the liver to
major types of lipoproteins which contain apoproteins. These determine whether they are neoplasms or non-neoplastic
are: high density lipoproteins (HDL), low density cysts.
lipoproteins (LDL) and very low density lipoproteins
(VLDL). iii) To provide US-guidance for FNAC or liver biopsy.
Blood lipids. Estimations of total serum cholesterol, 2. FNAC AND/OR PERCUTANEOUS LIVER BIOPSY.
triglycerides and lipoprotein fractions are frequently done Lastly, FNAC and percutaneous liver biopsy are employed
in patients with liver disease. to examine the microscopic changes of hepatic morphology
There is rise in total serum cholesterol in cholestasis, in various diseases. Both these tests are done after evaluation
probably due to retention of cholesterol which is normally of signs of obstruction since these tests are contraindicated
excreted in the bile (normal < 200 mg/dl). Serum triglyceride in cholestasis. FNAC and liver biopsy are otherwise easily
is also elevated in cholestasis. performed bedside tests of value. Their main indications are
Values are lowered in acute and chronic diffuse liver as follows:
diseases and in malnutrition. i) hepatocellular disease of unknown cause;
SECTION III
ii) suspected cases of chronic hepatitis;
3. CARBOHYDRATE METABOLISM. The liver plays a iii) hepatomegaly of various etiologies;
central role in carbohydrate metabolism. Blood glucose level iv) splenomegaly of unknown cause;
is lowered in fulminant acute hepatic necrosis. In chronic v) fever of unknown cause; and
liver disease, there is impaired glucose tolerance and relative vi) SOLs visualised in radiologic examination
insulin resistance.
JAUNDICE—GENERAL
IV. IMMUNOLOGIC TESTS
Jaundice or icterus refers to the yellow pigmentation of the
Liver diseases are associated with various immunologic skin or sclerae by bilirubin (page 42). Bilirubin pigment has
abnormalities which may be nonspecific immunologic reac- high affinity for elastic tissue and hence jaundice is
tions or may be antibodies against specific etiologic agents.
Systemic Pathology
particularly noticeable in tissues rich in elastin content.
1. NONSPECIFIC IMMUNOLOGIC REACTIONS. These Jaundice is the result of elevated levels of bilirubin in the
include the following: blood termed hyperbilirubinaemia. Normal serum bilirubin
i) Smooth muscle antibody to actin component of muscle is concentration ranges from 0.3-1.3 mg/dl, about 80% of which
formed in certain hepatic disorders with hepatic necrosis. It is unconjugated. Jaundice becomes clinically evident when
appears that hepatocytes have a protein which is the total serum bilirubin exceeds 2 mg/dl. A rise of serum
immunologically similar to actin. bilirubin between the normal and 2 mg/dl is generally not
ii) Mitochondrial antibody develops in patients with primary accompanied by visible jaundice and is called latent jaundice.
biliary cirrhosis. Before considering the features and types of jaundice, it
iii) Antinuclear antibody is present in some patients of chro- is essential to review the normal bilirubin metabolism.
nic hepatitis. The LE cell test may be positive in these cases.
NORMAL BILIRUBIN METABOLISM
2. ANTIBODIES TO SPECIFIC ETIOLOGIC AGENTS.
These vary according to the etiologic agent causing the liver Normal metabolism of bilirubin can be conveniently
cell injury. described under 4 main headings—source, transport, hepatic
i) Hepatitis B surface antigen (HBsAg) can be demonstrated phase and intestinal phase as illustrated schematically earlier
in cases of serum hepatitis. A confirmed positive test for in Chapter 12 (see Fig. 12.9, page 291).
HBsAg is definite proof of hepatitis B infection. 1. SOURCE OF BILIRUBIN. About 80-85% of the bilirubin
ii) Hepatitis B core antibody (HBc) can be detected in all is derived from the catabolism of haemoglobin present in
patients with hepatitis B. senescent red blood cells. The destruction of effete
erythrocytes at the end of their normal lifespan of 120 days 597
takes place in the reticuloendothelial system in the bone
marrow, spleen and liver. The remaining 15-20% of the
bilirubin comes partly from non-haemoglobin haem-
containing pigments such as myoglobin, catalase and
cytochromes, and partly from ineffective erythropoiesis. In
either case, haem moiety is formed which is converted to
biliverdin by microsomal haem oxygenase for which oxygen
and NADPH are essential requirements. Bilirubin is formed
from biliverdin by biliverdin reductase.
2. TRANSPORT OF BILIRUBIN. Bilirubin on release from
macrophages circulates as unconjugated bilirubin in plasma
tightly bound to albumin. Certain drugs such as
sulfonamides and salicylates compete with bilirubin for
albumin binding and displace bilirubin from albumin, thus
facilitating bilirubin to enter into the brain in neonates and
increase the risk of kernicterus. Bilirubin is found in body
fluids in proportion to their albumin content such as in CSF,
joint effusions, cysts etc.
3. HEPATIC PHASE. On coming in contact with the
hepatocyte surface, unconjugated bilirubin is preferentially
metabolised which involves 3 steps: hepatic uptake,
conjugation and secretion in bile.
i) Hepatic uptake: Albumin-bound unconjugated bilirubin
upon entry into the hepatocyte, is dissociated into bilirubin CHAPTER 21
and albumin. The bilirubin gets bound to cytoplasmic protein
glutathione-S-transferase (GST) (earlier called ligandin).
ii) Conjugation: Unconjugated bilirubin is not water-soluble
but is alcohol-soluble and is converted into water-soluble
compound by conjugation. Conjugation occurs in
endoplasmic reticulum and involves conversion to bilirubin
mono- and diglucuronide by the action of microsomal
enzyme, bilirubin- UDP-glucuronosyl transferase (Fig. 21.3).
The process of conjugation can be induced by drugs like Figure 21.3 Schematic representation of hepatic phase of bilirubin
transport.
phenobarbital.
Conjugated bilirubin is bound to albumin in two forms:
reversible and irreversible. Reversible binding is similar to The major differences between unconjugated and
that of unconjugated bilirubin. However, when present in conjugated bilirubin are summarised in Table 21.2.
serum for a long time (e.g. in cholestasis, long-standing
biliary obstruction, chronic active hepatitis), conjugated CLASSIFICATION AND FEATURES OF JAUNDICE
bilirubin is bound to albumin irreversibly and is termed delta The Liver, Biliary Tract and Exocrine Pancreas
bilirubin or biliprotein. This irreversible conjugated delta Based on pathophysiology, jaundice may result from one or
bilirubin is not excreted by the kidney, and remains more of the following mechanisms:
detectable in serum for sufficient time after recovery from 1. Increased bilirubin production
the diseases listed above. 2. Decreased hepatic uptake
3. Decreased hepatic conjugation
iii) Secretion into bile: Conjugated (water-soluble) bilirubin 4. Decreased excretion of bilirubin into bile
is rapidly transported directly into bile canaliculi by energy- Accordingly, a simple age-old classification of jaundice
dependent process and then excreted into the bile.
was to divide it into 3 predominant types: pre-hepatic
4. INTESTINAL PHASE. Appearance of conjugated (haemolytic), hepatic, and post-hepatic cholestatic. However,
bilirubin in the intestinal lumen is followed by either direct hyperbilirubinaemia due to first three mechanisms is mainly
excretion in the stool as stercobilinogen which imparts the unconjugated while the last variety yields mainly conjugated
normal yellow colour to stool, or may be metabolised to hyperbilirubinaemia. Hence, currently pathophysiologic
urobilinogen by the action of intestinal bacteria. Conjugated classification of jaundice is based on predominance of the
bilirubin is normally not reabsorbable whereas its metabolic type of hyperbilirubinaemia. A simple test to determine
product, urobilinogen, is reabsorbed from the small intestine whether hyperbilirubinaemia is of unconjugated or
and reaches enterohepatic circulation. Some of the absorbed conjugated variety is to determine whether bilirubin is
urobilinogen in resecreted by the liver into the bile while present in urine or not; its absence in urine suggests
the rest is excreted in the urine as urobilinogen. unconjugated hyperbilirubinaemia since unconjugated
598
TABLE 21.2: Major Differences between Unconjugated and Conjugated Bilirubin.
Feature Unconjugated Bilirubin Conjugated Bilirubin
1. Normal serum level More Less (less than 0.25 mg/dl)
2. Water solubility Absent Present
3. Affinity to lipids Present Absent
(alcohol solubility)
4. Serum albumin binding High Low
5. van den Bergh reaction Indirect Direct
(Total minus direct)
6. Renal excretion Absent Present
7. Bilirubin albumin covalent Absent Present
complex formation
8. Affinity to brain tissue Present (Kernicterus) Absent
bilirubin is not filtered by the glomerulus. The presence of 1. INCREASED BILIRUBIN PRODUCTION (HAEMO-
bilirubin in the urine is evidence of conjugated hyper- LYTIC, ACHOLURIC OR PREHEPATIC JAUNDICE). This
bilirubinaemia. results from excessive red cell destruction as occurs in intra-
Based on these mechanisms, the pathogenesis and main and extravascular haemolysis or due to ineffective
features of the two predominant forms of hyperbiliru- erythropoiesis. There is increased release of haemoglobin
binaemia are discussed below (Table 21.3). from excessive breakdown of red cells that leads to
overproduction of bilirubin. Hyperbilirubinaemia develops
I. Predominantly Unconjugated Hyperbilirubinaemia when the capacity of the liver to conjugate large amount of
bilirubin is exceeded. In premature infants, the liver is defi-
This form of jaundice can result from the following three sets cient in enzyme necessary for conjugation while the rate of
of conditions: red cell destruction is high. This results in icterus neonatorum
which is particularly severe in haemolytic disease of the
SECTION III
newborn due to maternal isoantibodies (Chapter 13). Since
TABLE 21.3: Pathophysiologic Classification of Jaundice. there is predominantly unconjugated hyperbilirubinaemia
in such cases, there is danger of permanent brain damage in
I. PREDOMINANTLY UNCONJUGATED HYPERBILIRUBINAEMIA
these infants from kernicterus when the serum level of
1. Increased bilirubin production (Haemolytic, acholuric or unconjugated bilirubin exceeds 20 mg/dl.
prehepatic jaundice) Laboratory data in haemolytic jaundice, in addition to
• Intra- and extravascular haemolysis predominant unconjugated hyperbilirubinaemia, reveal
• Ineffective erythropoiesis
normal serum levels of transaminases, alkaline phosphatase
2. Decreased hepatic uptake and proteins. Bile pigment being unconjugated type is absent
• Drugs from urine (acholuric jaundice). However, there is dark
• Prolonged starvation brown colour of stools due to excessive faecal excretion of
Systemic Pathology
• Sepsis bile pigment and increased urinary excretion of urobilinogen.
3. Decreased bilirubin conjugation 2. DECREASED HEPATIC UPTAKE. The uptake of
• Hereditary disorders (e.g. Gilbert’s syndrome, Crigler-Najjar bilirubin by the hepatocyte that involves dissociation of the
syndrome)
• Acquired defects (e.g. drugs, hepatitis, cirrhosis) pigment from albumin and its binding to cytoplasmic
• Neonatal jaundice protein, GST or ligandin, may be deranged in certain
conditions e.g. due to drugs, prolonged starvation and sepsis.
II. PREDOMINANTLY CONJUGATED HYPERBILIRUBINAEMIA
(CHOLESTASIS) 3. DECREASED BILIRUBIN CONJUGATION. This
1. Intrahepatic cholestasis (Impaired hepatic excretion) mechanism involves deranged hepatic conjugation due to
• Hereditary disorders or ‘pure cholestasis’ (e.g. Dubin-Johnson defect or deficiency of the enzyme, glucuronosyl transferase.
syndrome, Rotor’s syndrome, fibrocystic disease of pancreas, This can occur in certain inherited disorders of the enzyme
benign familial recurrent cholestasis, intrahepatic atresia, (e.g. Gilbert’s syndrome and Crigler-Najjar syndrome), or
cholestatic jaundice of pregnancy) acquired defects in its activity (e.g. due to drugs, hepatitis,
• Acquired disorders or ‘hepatocellular cholestasis’ (e.g. viral cirrhosis). However, hepatocellular damage causes deranged
hepatitis, drugs, alcohol-induced injury, sepsis, cirrhosis)
excretory capacity of the liver more than its conjugating
2. Extrahepatic cholestasis (Extrahepatic biliary obstruction) capacity (see below). The physiologic neonatal jaundice is also
• Mechanical obstruction (e.g. gallstones, inflammatory strictures, partly due to relative deficiency of UDP-glucuronosyl
carcinoma head of pancreas, tumours of bile ducts, sclerosing transferase in the neonatal liver and is partly as a result of
cholangitis, congenital atresia of extrahepatic ducts)
increased rate of red cell destruction in neonates.
599
Figure 21.4 Salient features in morphology of liver in intra- and extrahepatic cholestasis. A, Intrahepatic cholestasis is characterised by
elongated bile plugs in the canaliculi of hepatocytes at the periphery of the lobule. B, Extrahepatic cholestasis shows characteristic bile lakes due
to rupture of canaliculi in the hepatocytes in the centrilobular area.
II. Predominantly Conjugated Hyperbilirubinaemia Liver biopsy in cases with intrahepatic cholestasis reveals
(Cholestasis) milder degree of cholestasis than the extrahepatic disorders
(Fig. 21.4,A). The biliary canaliculi of the hepatocytes are
This form of hyperbilirubinaemia is defined as failure of
normal amounts of bile to reach the duodenum. Morpho- dilated and contain characteristic elongated green-brown bile
plugs. The cytoplasm of the affected hepatocytes shows
logically, cholestasis means accumulation of bile in liver cells feathery degeneration. Canalicular bile stasis eventually
and biliary passages. The defect in excretion may be within causes proliferation of intralobular ductules followed by
the biliary canaliculi of the hepatocyte and in the microscopic periportal fibrosis and produces a picture resembling biliary
bile ducts (intrahepatic cholestasis or medical jaundice), or there cirrhosis (page 625). CHAPTER 21
may be mechanical obstruction to the extrahepatic biliary
excretory apparatus (extrahepatic cholestasis or obstructive 2. EXTRAHEPATIC CHOLESTASIS. Extrahepatic choles-
jaundice). It is important to distinguish these two forms of tasis results from mechanical obstruction to large bile ducts
cholestasis since extrahepatic cholestasis or obstructive outside the liver or within the porta hepatis. The common
jaundice is often treatable with surgery, whereas the causes are gallstones, inflammatory strictures, carcinoma
intrahepatic cholestasis or medical jaundice cannot be head of pancreas, tumours of bile duct, sclerosing cholangitis
benefitted by surgery but may in fact worsen by the and congenital atresia of extrahepatic ducts. The obstruction
operation. Prolonged cholestasis of either of the two types may be complete and sudden with eventual progressive
may progress to biliary cirrhosis (page 625). obstructive jaundice, or the obstruction may be partial and
incomplete resulting in intermittent jaundice.
1. INTRAHEPATIC CHOLESTASIS. Intrahepatic The features of extrahepatic cholestasis (obstructive jaun-
cholestasis is due to impaired hepatic excretion of bile and dice), like in intrahepatic cholestasis, are: predominant
may occur from hereditary or acquired disorders. conjugated hyperbilirubinaemia, bilirubinuria, elevated
i) Hereditary disorders producing intrahepatic obstruction serum bile acids causing intense pruritus, high serum
to biliary excretion are characterised by ‘pure cholestasis’ e.g. alkaline phosphatase and hyperlipidaemia. However, there
in Dubin-Johnson syndrome, Rotor syndrome, fibrocystic are certain features which help to distinguish extrahepatic The Liver, Biliary Tract and Exocrine Pancreas
disease of pancreas, benign familial recurrent cholestasis, from intrahepatic cholestasis. In obstructive jaundice, there
intrahepatic atresia and cholestatic jaundice of pregnancy. is malabsorption of fat-soluble vitamins (A,D,E and K) and
ii) Acquired disorders with intrahepatic excretory defect of steatorrhoea resulting in vitamin K deficiency. Prolonged
bilirubin are largely due to hepatocellular diseases and hence prothrombin time in such cases shows improvement
are termed ‘hepatocellular cholestasis’ e.g. in viral hepatitis, following parenteral administration of vitamin K, whereas
alcoholic hepatitis, and drug-induced cholestasis such as hypoprothrombinaemia due to hepatocellular disease shows
from administration of chlorpromazine and oral no such improvement in prothrombin time with vitamin K
contraceptives. administration. The stools of such patients are clay-coloured
The features of intrahepatic cholestasis include: due to absence of bilirubin metabolite, stercobilin, in faeces
predominant conjugated hyperbilirubinaemia due to and there is virtual disappearance of urobilinogen from the
regurgitation of conjugated bilirubin into blood, biliru- urine. These patients may have fever due to high incidence
binuria, elevated levels of serum bile acids and consequent of ascending bacterial infections (ascending cholangitis).
pruritus, elevated serum alkaline phosphatase, Liver biopsy in cases with extrahepatic cholestasis shows
hyperlipidaemia and hypoprothrombinaemia. ‘Pure choles- more marked changes of cholestasis (Fig. 21.4,B). Since the
tasis’ can be distinguished from ‘hepatocellular cholestasis’ obstruction is in the extrahepatic bile ducts, there is
by elevated serum levels of transaminases in the latter due progressive retrograde extension of bile stasis into
to liver cell injury. intrahepatic duct system. This results in dilatation of bile
600 HEREDITARY NON-HAEMOLYTIC
TABLE 21.4: Causes of Neonatal Jaundice.
HYPERBILIRUBINAEMIAS
A. UNCONJUGATED HYPERBILIRUBINAEMIA
Hereditary non-haemolytic hyperbilirubinaemias are a small
1. Physiologic and prematurity jaundice
2. Haemolytic disease of the newborn and kernicterus (page group of uncommon familial disorders of bilirubin
340) metabolism when haemolytic causes have been excluded.
3. Congenital haemolytic disorders (page 314) The commonest is Gilbert’s syndrome; others are Crigler-
4. Perinatal complications (e.g. haemorrhage, sepsis) Najjar syndrome, Dubin-Johnson syndrome, Rotor’s
5. Gilbert’s syndrome syndrome and benign familial recurrent cholestasis. The
6. Crigler-Najjar syndrome (type I and II) features common to all these conditions are presence of
B. CONJUGATED HYPERBILIRUBINAEMIA icterus but almost normal liver function tests and no well-
defined morphologic changes except in Dubin-Johnson
1. Hereditary (Dubin-Johnson syndrome, Rotor’s syndrome)
2. Infections (e.g. hepatitis B, hepatitis C or non-A non-B hepatitis, syndrome. Gilbert’s syndrome and Crigler-Najjar syndrome
rubella, coxsackievirus, cytomegalovirus, echovirus, herpes are examples of hereditary non-haemolytic unconjugated
simplex, syphilis, toxoplasma, gram-negative sepsis) hyperbilirubinaemia, whereas Dubin-Johnson syndrome,
3. Metabolic (e.g. galactosaemia, alpha-1-antitrypsin deficiency, Rotor’s syndrome and benign familial recurrent cholestasis
cystic fibrosis, Niemann-Pick disease) are conditions with hereditary conjugated hyperbilirubinaemia.
4. Idiopathic (neonatal hepatitis, congenital hepatic fibrosis) These conditions are briefly described below. Their
5. Biliary atresia (intrahepatic and extrahepatic) distinguishing features are summarised in Table 21.5.
6. Reye’s syndrome
Gilbert’s Syndrome
ducts and rupture of canaliculi with extravasation of bile This is the commonest of the familial, genetically-determined
producing bile lakes. Since bile is toxic, the regions of bile diseases of the liver affecting 2-5% of the population. Gilbert’s
lakes are surrounded by focal necrosis of hepatocytes. Stasis syndrome is characterised by mild, benign, unconjugated
of bile predisposes to ascending bacterial infections with hyperbilirubinaemia (serum bilirubin 1-5 mg/dl) which is
accumulation of polymorphs around the dilated ducts not due to haemolysis. The condition is inherited as an
(ascending cholangitis). Eventually, there is proliferation of autosomal dominant character. The defect in bilirubin
bile ducts and the appearance may mimic biliary cirrhosis metabolism is complex and appears to be reduced activity
(page 625). of UDP-glucuronosyl transferase with decreased
SECTION III
conjugation, or an impaired hepatic uptake of bilirubin. The
NEONATAL JAUNDICE jaundice is usually mild and intermittent.
Jaundice appears in neonates when the total serum bilirubin MORPHOLOGIC FEATURES. There are no morphologic
is more than 3 mg/dl. It may be the result of unconjugated abnormalities in the liver except some increased lipofuscin
or conjugated hyperbilirubinaemia; the former being more pigment in centrilobular hepatocytes. The prognosis of
common. Important causes of neonatal jaundice are listed patients with Gilbert’s syndrome is excellent, though
in Table 21.4. Some of these conditions are considered below, chronic jaundice persists throughout life.
while others are discussed elsewhere in the relevant sections.
TABLE 21.5: Contrasting Features of Major Hereditary Non-haemolytic Hyperbilirubinaemias.
Systemic Pathology
Feature Gilbert’s Type 1 Type 2 Dubin-Johnson Rotor
Syndrome Crigler-Najjar Crigler-Najjar Syndrome Syndrome
Syndrome Syndrome
1. Inheritance Autosomal Autosomal Autosomal Autosomal Autosomal
dominant recessive dominant recessive recessive
2. Predominant Unconjugated Unconjugated Unconjugated Conjugated Conjugated
hyperbilirubinaemia
3. Intensity of Mild Marked Mild to moderate Mild Mild
jaundice (< 5 mg/dl) (>20 mg/dl) (<20 mg/dl) (<5 mg/dl) (< 5 mg/dl)
4. Basic defect ↓ UDP- Absence of UDP- ↓ UDP- Defect in canali- Deranged hepatic
glucuronosyl glucuronosyl glucuronosyl cular excretion storage
transferase transferase transferase (Prolonged BSP
activity excretion test)
5. Hepatic Normal (except Normal (except Normal Greenish-black Normal
morphology slightly increased mild canalicular pigment
lipofuscin) stasis)
6. Prognosis Excellent Poor (due to Good Excellent Excellent
kernicterus)
Crigler-Najjar Syndrome NEONATAL HEPATITIS 601
Crigler-Najjar syndrome is a rare form of familial non- Neonatal hepatitis, also termed giant cell hepatitis or
haemolytic jaundice with very high unconjugated hyper- neonatal hepatocellular cholestasis, is a general term used
bilirubinaemia. There are 2 forms of this condition: type I and for the constant morphologic change seen in conjugated
type II. hyperbilirubinaemia as a result of known infectious and
metabolic causes listed in Table 21.4, or may have an
Type I Crigler-Najjar syndrome. This is inherited as an idiopathic etiology. ‘Idiopathic’ neonatal hepatitis is more
autosomal recessive disorder. There is complete absence of common and accounts for 75% of cases. Though all the cases
conjugating enzyme UDP-glucuronosyl transferase in the with either known etiologies or idiopathic type are grouped
hepatocytes and hence no conjugated bilirubin is formed. together under neonatal hepatitis, all of them are not
There is extreme elevation of unconjugated bilirubin (usually necessarily inflammatory conditions, thus belying their
more than 20 mg/dl) with high risk of developing permanent nomenclature as ‘hepatitis’. The condition usually presents
CNS damage from kernicterus. The prognosis is generally in the first week of birth with jaundice, bilirubinuria, pale
fatal, with death coming from kernicterus usually in the first stools and high serum alkaline phosphatase.
year of life.
MORPHOLOGIC FEATURES. There are no significant MORPHOLOGIC FEATURES. Irrespective of the etio-
morphologic changes except some canalicular stasis. logy, there is morphologic similarity in all these cases. The
histologic features are as under:
Type II Crigler-Najjar syndrome. This is inherited as an 1. Loss of normal lobular architecture of the liver.
autosomal dominant disease. There is deficiency of enzyme 2. Presence of prominent multinucleate giant cells
UDP-glucuronosyl transferase but not complete absence. derived from hepatocytes.
Thus, unconjugated hyperbilirubinaemia is generally mild 3. Mononuclear inflammatory cell infiltrate in the portal
to moderate (usually less than 20 mg/dl). Occurrence of tracts with some periportal fibrosis.
kernicterus is exceptional and patients respond well to 4. Haemosiderosis.
phenobarbital therapy. 5. Cholestasis in small proliferated ductules in the portal
tract and between necrotic liver cells. CHAPTER 21
MORPHOLOGIC FEATURES. There are no morphologic
changes in the liver. BILIARY ATRESIAS
Biliary atresias, also called as infantile cholangiopathies, are a
Dubin-Johnson Syndrome
group of intrauterine developmental abnormalities of the
Dubin-Johnson syndrome is autosomal recessive disorder biliary system. Though they are often classified as congenital,
characterised by predominant conjugated hyperbilirubinaemia the abnormality of development in most instances is
(usually less than 5 mg/dl) with genetic defect in canalicular extraneous infection during the intrauterine development or
excretion of conjugated bilirubin. A prolonged BSP dye shortly after birth that brings about inflammatory destruction
excretion test is diagnostic of Dubin-Johnson syndrome of the bile ducts. The condition may, therefore, have various
(page 593). grades of destruction ranging from complete absence of bile
ducts termed atresia, to reduction in their number called
MORPHOLOGIC FEATURES. Grossly, the condition paucity of bile ducts.
differs from other forms of hereditary hyperbili- Depending upon the portion of biliary system involved,
rubinaemias in producing greenish-black pigmented liver. biliary atresias may be extrahepatic or intrahepatic.
Microscopically, The hepatocytes show dark-brown, The Liver, Biliary Tract and Exocrine Pancreas
melanin-like pigment in the cytoplasm, the exact nature Extrahepatic Biliary Atresia
of which is obscure but it is neither iron nor bile. Unrelated The extrahepatic bile ducts fail to develop normally so that
viral hepatitis mobilises the hepatic pigment of Dubin- in some cases the bile ducts are absent at birth, while in others
Johnson syndrome leading to its excretion in urine but the ducts may have been formed but start undergoing
the pigment reappears after recovery from viral hepatitis.
sclerosis in the perinatal period. It is common to have
multiple defects and other congenital lesions. Extrahepatic
The disease runs a benign course and does not interfere
with life. biliary atresia is found in 1 per 10,000 livebirths. Cholestatic
jaundice appears by the first week after birth. The baby has
severe pruritus, pale stools, dark urine and elevated serum
Rotor’s Syndrome
transaminases. In some cases, the condition is correctable
This is another form of familial conjugated hyperbilirubinaemia by surgery, while in vast majority the atresia is not correc-
with mild chronic jaundice but differs from Dubin-Johnson table and in such cases hepatic portoenterostomy (Kasai
syndrome in having no brown pigment in the liver cells. The procedure) or hepatic transplantation must be considered.
disease is inherited as an autosomal recessive character. The Death is usually due to intercurrent infection, liver failure,
defect probably lies in intrahepatic storage of bilirubin but and bleeding due to vitamin K deficiency or oesophageal
the exact protein abnormality is not known. varices. Cirrhosis and ascites are late complications
Rotor’s syndrome has an excellent prognosis. appearing within 2 years of age.
602 MORPHOLOGIC FEATURES. Grossly, the liver is MORPHOLOGIC FEATURES. Grossly, the liver is enlar-
enlarged and dark green. The atretic segments of biliary ged and yellowish-orange.
system are reduced to cord-like structures. Microscopically, hepatocytes show small droplets of
Histologically, the condition must be distinguished from neutral fat in their cytoplasm (microvesicular fat). Similar
idiopathic neonatal hepatitis as surgical treatment is fatty change is seen in the renal tubular epithelium and
possible in extrahepatic biliary atresia but not in the latter. in the cells of skeletal muscles and heart. The brain shows
Besides, α-1-antitrypsin deficiency also produces similar oedema and sometimes focal necrosis of neurons.
appearance in liver biopsy. The main histologic features
are as under: HEPATIC FAILURE
1. Inflammation and fibrous obliteration of the
extrahepatic ducts with absence of bile in them. Though the liver has a marked regenerative capacity and a
2. Ductular proliferation and periductular inflammation. large functional reserve, hepatic failure may develop from
3. Cholestasis and bile thrombi in the portal area. severe acute and fulminant liver injury with massive necrosis
4. Periportal fibrosis and later secondary biliary cirrhosis of liver cells (acute hepatic failure), or from advanced chronic
(page 625). liver disease (chronic hepatic failure). Acute hepatic failure
5. Transformation of hepatic parenchyma to neonatal develops suddenly with severe impairment of liver functions
(giant cell) hepatitis in 15% of cases. whereas chronic liver failure comes insidiously. The
prognosis is much worse in acute hepatic failure than that
Intrahepatic Biliary Atresia in chronic liver failure.
Intrahepatic biliary atresia is characterised by biliary ETIOLOGY. Acute and chronic hepatic failure result from
hypoplasia so that there is paucity of bile ducts rather than different causes:
their complete absence. The condition probably has its origin Acute (fulminant) hepatic failure occurs most frequently
in viral infection acquired during intrauterine period or in in acute viral hepatitis. Other causes are hepatotoxic drug
the neonatal period. Cholestatic jaundice usually appears reactions (e.g. anaesthetic agents, nonsteroidal anti-
within the first few days of birth and is characterised by high inflammatory drugs, anti-depressants), carbon tetrachloride
serum bile acids with associated pruritus, and poisoning, acute alcoholic hepatitis, mushroom poisoning
hypercholesterolaemia with appearance of xanthomas by and pregnancy complicated with eclampsia.
first year of life. Hepatic as well as urinary copper Chronic hepatic failure is most often due to cirrhosis.
SECTION III
concentrations are elevated. In some cases, intrahepatic Other causes include chronic active hepatitis, chronic
biliary atresia is related to α-1-antitrypsin deficiency. cholestasis (cholestatic jaundice) and Wilson’s disease.
MORPHOLOGIC FEATURES. The microscopic features MANIFESTATIONS. In view of the diverse functions
are as follows: performed by the liver, the syndrome of acute or chronic
1. Paucity of intrahepatic bile ducts. hepatic failure produces complex manifestations. The major
2. Cholestasis. manifestations are briefly discussed below and
3. Increased hepatic copper. diagrammatically illustrated in Fig. 21.5.
4. Inflammation and fibrosis in the portal area, 1. Jaundice. Jaundice usually reflects the severity of liver
eventually leading to cirrhosis. cell damage since it occurs due to failure of liver cells to
metabolise bilirubin. In acute failure such as in viral hepatitis,
Systemic Pathology
REYE’S SYNDROME jaundice nearly parallels the extent of liver cell damage, while
in chronic failure such as in cirrhosis jaundice appears late
Reye’s syndrome is defined as an acute postviral syndrome
of encephalopathy and fatty change in the viscera. The and is usually of mild degree.
syndrome may follow almost any known viral disease but 2. Hepatic encephalopathy (Hepatic coma). Neuro-
is most common after influenza A or B and varicella. Viral psychiatric syndrome may complicate liver disease of both
infection may act singly, but more often its effect is modified acute and chronic types. The features include disturbed
by certain exogenous factors such as by administration of consciousness, personality changes, intellectual
salicylates, aflatoxins and insecticides. These effects cause deterioration, low slurred speech, flapping tremors, and
mitochondrial injury and decreased activity of mitochondrial finally, coma and death. The genesis of CNS manifestations
enzymes in the liver. This eventually leads to rise in blood in liver disease is by toxic products not metabolised by the
ammonia and accumulation of triglycerides within diseased liver. The toxic products may be ammonia and other
hepatocytes. nitrogenous substances from intestinal bacteria which reach
The patients are generally children between 6 months and the systemic circulation without detoxification in the
15 years of age. Within a week after a viral illness, the child damaged liver and thus damage the brain. Advanced cases
develops intractable vomiting and progressive neurological of hepatic coma have poor prognosis but may respond
deterioration due to encephalopathy, eventually leading to favourably to hepatic transplantation.
stupor, coma and death. Characteristic laboratory findings 3. Hyperkinetic circulation. All forms of hepatic failure are
are elevated blood ammonia, serum transaminases, bilirubin associated with a hyperkinetic circulation characterised by
and prolonged prothrombin time. peripheral vasodilatation, increased splanchnic blood flow
intravascular coagulation (consumption coagulopathy), 603
thrombocytopenia and presence of fibrin degradation
products in the blood.
7. Ascites and oedema. Chronic liver failure due to cirrhosis
may result in portal hypertension and ascites (page 630).
Decreased synthesis of albumin by the liver resulting in
hypoproteinaemia and consequent fall in plasma oncotic
pressure, increased hydrostatic pressure due to portal
hypertension and secondary hyperaldosteronism, contribute
to the development of ascites and oedema in these patients.
8. Endocrine changes. Endocrine changes may be found in
association with chronic hepatic failure. The changes are
more common in alcoholic cirrhosis in active reproductive
life. In the male, the changes are towards feminisation such
as gynaecomastia and hypogonadism. In the female, the
changes are less towards masculinisation but atrophy of
gonads and breasts occurs. The underlying mechanism
appears to be changed end-organ sensitiveness to sex
hormones in cirrhosis.
9. Skin changes. In alcoholic cirrhosis ‘arterial spiders’
having radiating small vessels from a central arteriole are
frequent in the vascular region drained by superior vena cava
Figure 21.5 Complications of hepatic failure. such as in the neck, face, forearms and dorsum of hands.
Less frequently, palmar erythema, especially in the hypothenar
and thenar eminences and on the pulps of the fingers, is
and increased cardiac output. There is increased splenic flow observed in chronic liver disease. CHAPTER 21
but reduced renal blood flow resulting in impaired renal
cortical perfusion. These changes result in tachycardia, low 10. Foetor hepaticus. A sweetish pungent smell of the breath
blood pressure and reduced renal function. is found in severe cases of acute and chronic hepatocellular
diseases. It appears to be of intestinal origin, possibly due to
4. Hepatorenal syndrome. The term hepatorenal syndrome failure of the liver to detoxify sulfur-containing substances
is applied to patients of both acute and chronic hepatic failure absorbed from the gut.
who develop renal failure as well, in the absence of clinical,
laboratory or morphologic evidence of other causes of renal CIRCULATORY DISTURBANCES
dysfunction. Hepatorenal syndrome develops in about 10%
cases of acute and chronic liver diseases. The acute renal Vascular disorders of general nature involving the liver such
failure is usually associated with oliguria and uraemia but as chronic passive congestion and infarction have already
with good tubular function. The histology of kidney is been discussed in Chapter 5. Hepatic and portal venous
virtually normal, suggesting functional defect for the renal obstruction and hepatic arterial obstruction are considered
failure. The pathogenesis of the syndrome is poorly here.
understood but appears to be initiated by effective reduction
of the renal blood flow (effective hypovolaemia) as a I. HEPATIC VENOUS OBSTRUCTION The Liver, Biliary Tract and Exocrine Pancreas
consequence of systemic vasodilatation and pooling of blood The central veins of lobules of the liver are tributaries of the
in portal circulation. The renal failure in the hepatorenal hepatic veins. In the normal liver, there are no anastomoses
syndrome is reversible with improvement in hepatic between hepatic vein and portal vein but in cirrhotic liver
function. there are such anastomoses. Normal pressure in the free
Diagnosis of hepatorenal syndrome should be made only hepatic vein is about 6 mmHg.
after excluding other causes producing concomitant damage Two uncommon diseases produced by obstruction of the
to both the organs, circulatory failure leading to acute tubular hepatic veins are Budd-Chiari syndrome (hepatic vein
necrosis and other forms of reversible tubular damage.
thrombosis) and hepatic veno-occlusive disease.
5. Hepatopulmonary syndrome. The pulmonary changes
in chronic hepatic failure such as in cirrhosis consist of Budd-Chiari Syndrome (Hepatic Vein Thrombosis)
pulmonary vasodilatation with intra-pulmonary
arteriovenous shunting. This results in ventilation-perfusion Budd-Chiari syndrome in its pure form consists of slowly
inequality that may lead to impaired pulmonary function, developing thrombosis of the hepatic veins and the adjacent
clubbing of fingers and sometimes cyanosis. inferior vena cava, while some workers include hepatic veno-
occlusive disease (described below) in this syndrome.
6. Coagulation defects. Impaired synthesis of a number of
coagulation factors by the diseased liver may result in ETIOLOGY. The etiology of hepatic venous thrombosis in
coagulation disorders. These include disseminated about a third of cases is unknown (idiopathic), while in the
604 remaining cases various causes associated with increased The effects of portal venous obstruction depend upon
thrombotic tendencies are attributed to polycythaemia vera, the site of obstruction. The most important effect, irrespective
paroxysmal nocturnal haemoglobinuria, oral contraceptives, of the site of occlusion or cause, is portal hypertension and
pregnancy, postpartum state, intra-abdominal cancers (e.g. its manifestations (page 630). If the obstruction is in the
hepatocellular carcinoma), chemotherapy, radiation and extrahepatic portal vein along with extension of occlusion
myeloproliferative diseases. Formation of membranous into splenic vein, it may result in venous infarction of the
webs, probably congenital or as a consequence of organised bowel. Pylephlebitis may be followed by multiple pyaemic
thrombosis, in the suprahepatic portion of inferior vena cava liver abscesses.
is another important cause.
Peliosis Hepatis
MORPHOLOGIC FEATURES. Grossly, the liver is enlar- Although sinusoidal dilatation can occur secondary to many
ged, swollen, red-purple and has a tense capsule. liver diseases, peliosis hepatis is an uncommon condition of
Histologically, the changes in sudden hepatic vein primary sinusoidal dilatation that results in blockage of blood
occlusion are those of centrilobular congestion, necrosis outflow and may result in massive intraperitoneal
and rupture of sinusoids into the space of Disse. In slowly haemorrhage. Although exact etiology is not known, peliosis
developing thrombosis, the changes are more chronic and hepatis and another related condition, bacillary angiomatosis
include fibrosing reaction in the centrilobular zone that (page 413), have been found to occur in HIV-infected patients
may progress to cardiac cirrhosis.
whose CD4+ T cell counts fall below 100/μl. Opportunistic
infection with Bartonella henselae in poor hygienic conditions
CLINICAL FEATURES. Budd-Chiari syndrome is clinically in these cases results in blood-filled cysts in liver partly lined
characterised by either an acute form or chronic form by endothelial cells and having mixed inflammatory cells in
depending upon the speed of occlusion. a fibromyxoid background.
In the acute form, the features are abdominal pain, Etiologic association of peliosis hepatis with consumption
vomiting, enlarged liver, ascites and mild icterus. of anabolic steroids and oral contraceptives has also been
In the more usual chronic form, the patients present with suggested and is self-limiting with withdrawal of the
pain over enlarged tender liver, ascites and other features of offending agent.
portal hypertension.
The acute form of illness leads to acute hepatic failure III. HEPATIC ARTERIAL OBSTRUCTION
SECTION III
and death, whereas in chronic form the patient may live for Diseases from obstruction of the hepatic artery are
months to a few years.
uncommon. Rarely, accidental ligation of the main hepatic
Hepatic Veno-occlusive Disease artery or its branch to right lobe may be followed by fatal
infarction. Obstruction of the small intrahepatic arterial
Hepatic veno-occlusive disease consists of intimal thickening, branches usually does not produce any effects because of
stenosis and obliteration of the terminal central veins and good collateral circulation.
medium-sized hepatic veins. The venous occlusion results
in pathologic changes similar to those of Budd-Chiari
syndrome and can be distinguished from the latter by LIVER CELL NECROSIS
demonstration of absence of thrombosis in the major hepatic All forms of injury to the liver such as microbiologic, toxic,
veins. circulatory or traumatic, result in necrosis of liver cells. The
Systemic Pathology
The cause and stimulus for hepatic veno-occlusive extent of involvement of hepatic lobule in necrosis varies.
disease are obscure. The condition is more widespread in Accordingly, liver cell necrosis is divided into 3 types: diffuse
countries such as Africa, India and certain other tropical (submassive to massive), zonal and focal.
countries where ‘bush tea’ (medicinal tea) is consumed that
contains hepatotoxic alkaloids. The disease has also been 1. DIFFUSE (SUBMASSIVE TO MASSIVE) NECROSIS.
found in association with administration of antineoplastic When there is extensive and diffuse necrosis of the liver
drugs and immunosuppressive therapy. involving all the cells in groups of lobules, it is termed
diffuse, or submassive to massive necrosis. It is most
II. PORTAL VENOUS OBSTRUCTION commonly caused by viral hepatitis or drug toxicity.
Obstruction of the portal vein may occur within the 2. ZONAL NECROSIS. Zonal necrosis is necrosis of
intrahepatic course or in extrahepatic site. hepatocytes in 3 different zones of the hepatic lobule (page
Intrahepatic cause of portal venous occlusion is hepatic 592). Accordingly, it is of 3 types; each type affecting
cirrhosis as the commonest and most important, followed in respective zone is caused by different etiologic factors:
decreasing frequency by tumour invasion, congenital hepatic i) Centrilobular necrosis is the commonest type involving
fibrosis and schistosomiasis. hepatocytes in zone 3 (i.e. located around the central vein).
Extrahepatic causes of portal vein obstruction are intra- Centrilobular necrosis is characteristic feature of ischaemic
abdominal cancers, intra-abdominal sepsis, direct invasion injury such as in shock and CHF since zone 3 is farthest from
by tumour, myeloproliferative disorders and upper the blood supply. Besides, it also occurs in poisoning with
abdominal surgical procedure followed by thrombosis. chloroform, carbon tetrachloride and certain drugs.
ii) Midzonal necrosis is uncommon and involves zone 2 of Hepatitis B virus (HBV), causing a parenterally transmitted 605
the hepatic lobule. This pattern of necrosis is seen in yellow disease that may become chronic.
fever and viral hepatitis. In viral hepatitis, some of the Hepatitis C virus (HCV), previously termed non-A, non-B
necrosed hepatocytes of the mid-zone are transformed into (NANB) hepatitis virus involved chiefly in transfusion-
acidophilic, rounded Councilman bodies. related hepatitis.
iii) Periportal (peripheral) necrosis is seen in zone 1 Hepatitis delta virus (HDV) which is sometimes associated
involving the parenchyma closest to the arterial and portal as superinfection with hepatitis B infection.
blood supply. Since zone 1 is most well perfused, it is most Hepatitis E virus (HEV), causing water-borne infection.
vulnerable to the effects of circulating hepatotoxins e.g. in
phosphorus poisoning and eclampsia. Hepatitis G virus (HGV), is a recently discovered
transfusion-transmitted hepatotropic virus but is not known
3. FOCAL NECROSIS. This form of necrosis involves small to cause hepatitis.
groups of hepatocytes irregularly distributed in the hepatic All these human hepatitis viruses are RNA viruses except
lobule. Focal necrosis is most often caused by microbiologic HBV which is a DNA virus.
infections. These include viral hepatitis, miliary tuberculosis, Though a number of other viral diseases such as infection
typhoid fever and various other forms of bacterial, viral and with Epstein-Barr virus (in infectious mononucleosis),
fungal infections. Focal necrosis may also occur in drug- arbovirus (in yellow fever), cytomegalovirus, herpes simplex
induced hepatitis. and several others affect the liver but the changes produced
by them are nonspecific; the term ‘viral hepatitis’ is strictly
VIRAL HEPATITIS applied to infection of the liver by the hepatitis viruses.
The term viral hepatitis is used to describe infection of the ETIOLOGIC CLASSIFICATION
liver caused by hepatotropic viruses. Currently there are 5 Based on the etiologic agent, viral hepatitis is currently
main varieties of these viruses and a sixth poorly- classified into 6 etiologic types—hepatitis A, hepatitis B,
characterised virus, causing distinct types of viral hepatitis:
hepatitis C, hepatitis D, hepatitis E and hepatitis G. The
Hepatitis A virus (HAV), causing a faecally-spread self- contrasting features of major types are presented in CHAPTER 21
limiting disease. Table 21.6.
TABLE 21.6: Features of Various Types of Hepatitis Viruses.
Feature Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
1. Agent HAV HBV HCV HDV HEV
2. Year identified 1973 1965 1989 1977 1980
3. Viral particle 27 nm 42 nm 30-60 nm 35-37 nm 32-34 nm
4. Genome RNA, ss, linear DNA, ss/ds RNA, ss, linear RNA, ss, circular RNA, ss, linear
circular
5. Morphology Icosahedral Double-shelled, Enveloped Enveloped, replication Icosahedral,
non-enveloped enveloped defective non-enveloped
6. Spread Faeco-oral Parenteral, Parenteral, Parenteral, close Water-borne
close contact close contact contact The Liver, Biliary Tract and Exocrine Pancreas
7. Incubation 15-45 days 30-180 days 20-90 days 30-50 days 15-60 days
period (In superinfection)
8. Antigen(s) HAV HBsAg HCV RNA HBsAg HEV
HBcAg C 100-3 HDV
HBeAg C 33c
HBxAg NS5
9. Antibodies anti-HAV anti-HBs anti-HCV anti-HBs anti-HEV
anti-HBc anti-HDV
anti-HBe
10. Severity Mild Occasionally severe Moderate Occasionally severe Mild
11. Chronic None Occasional Common Common None
hepatitis
12. Carrier state None <1% <1% 1-10% Unknown
13. Hepatocellular No + + ± None
carcinoma
14. Prognosis Excellent Worse with age Moderate Acute good; chronic poor Good
(ss= single-stranded; ss/ds= partially single-stranded partially double-stranded)
606 products, intravenous drug addicts, patients treated by renal
dialysis and hospital workers exposed to blood, and by
intimate physical contact such as from mother to child and
by sexual contact. The disease may occur at any age. HBV
infection causes more severe form of illness that includes:
acute hepatitis B, chronic hepatitis, progression to cirrhosis,
fulminant hepatitis and an asymptomatic carrier stage. HBV
plays some role in the development of hepatocellular
carcinoma as discussed later (page 634).
HEPATITIS B VIRUS (HBV). The etiologic agent for
hepatitis B, HBV, is a DNA virus which has been extensively
studied. Electron microscopic studies on serum of patients
infected with HBV show 3 forms of viral particles of 2 sizes:
Figure 21.6 Sequence of appearance of antibodies to HAV. small (spheres and tubules/filaments) and large (spheres)
as under:
Hepatitis A i) Small particles are most numerous and exist in two forms—
as 22 nm spheres, and as tubules 22 nm in diameter and
Infection with HAV causes hepatitis A (infectious hepatitis). 100 nm long. These are antigenically identical to envelope
Hepatitis A is responsible for 20-25% of clinical hepatitis in protein of HBV and represent excess of viral envelope protein
the developing countries of the world but the incidence is referred as hepatitis B surface antigen (HBsAg).
much lower in the developed countries. Hepatitis A is
usually a benign, self-limiting disease and has an incubation ii) Large particles, 42 nm in diameter, are double-shelled
period of 15-45 days. The disease occurs in epidemic form spherical particles, also called as Dane particles. These are
as well as sporadically. It is usually spread by faeco-oral about 100 to 1000 times less in number in serum compared
route. Parenteral transmission is extremely rare. The spread to small 22 nm particles and represent intact virion of HBV.
is related to close personal contact such as in overcrowding, The genomic structure of HBV is quite compact and
poor hygiene and poor sanitation. Most frequently affected complex. The HBV DNA consists of 4 overlapping genes
age is 5-14 years; adults are often infected by spread from which encode for multiple proteins (Fig 21.7):
children. 1. S gene codes for the surface envelope protein, hepatitis B
SECTION III
surface antigen (HBsAg); this protein product is termed major
HEPATITIS A VIRUS (HAV). The etiologic agent for protein. HBsAg is present on the outer surface of the large
hepatitis A, HAV, is a small, 27 nm diameter, icosahedral spherical particles as well as in small spherical and tubular
non-enveloped, single-stranded RNA virus. Viral genome structures. Pre-S1 and pre-S2 regions of genome are upstream
has been characterised but only a single serotype has been of S gene and code for pre-S gene protein products that
identified. HAV infection can be transmitted to primates and includes receptor on the HBV surface and for hepatocyte
the virus can be cultivated in vitro. Inactivation of viral membrane proteins. The protein product of S-gene plus
activity can be achieved by boiling for 1 minute, by ultraviolet
radiation, or by contact with formaldehyde and chlorine. The
virus is present in the liver cells, bile, stool and blood during
the incubation period and in pre-icteric phase but viral
Systemic Pathology
shedding diminishes after the onset of jaundice. Chronic
carriers have not been identified for HAV infection.
PATHOGENESIS. The mechanism by which HAV infection
causes hepatitis A is poorly understood. An immunologic
basis is suspected but the evidence in support is indirect in
the form of immunologic markers but not direct demons-
tration of the etiologic agent in the affected hepatocytes.
These markers are as follows (Fig. 21.6):
1. IgM anti-HAV antibody appears in the serum at the onset
of symptoms of acute hepatitis A.
2. IgG anti-HAV antibody is detected in the serum after acute
illness and remains detectable indefinitely. It gives life-long
protective immunity against reinfection with HAV.
Hepatitis B
Hepatitis B (serum hepatitis) caused by HBV infection has a
longer incubation period (30-180 days) and is transmitted
parenterally such as in recipients of blood and blood Figure 21.7 Genomic structure of hepatitis B virus (Dane particle).
adjacent pre-S2 region is the middle protein, while the protein 607
products of pre-S1 plus pre-S2 regions is the large protein.
Large protein coming from both pre-S proteins is rich in
complete virions.
2. P gene is the largest and codes for DNA polymerase.
3. C gene codes for two nucleocapsid proteins, HBeAg and a
core protein termed HBcAg.
4. X gene codes for HBxAg which is a small non-particulate
protein. HbxAg has a role in transactivation the transcription
of both viral and cellular genes. The processes transactivated
by X-genes include signal-transduction pathways, increased
replication of HBV DNA, replication of other viruses
including HIV, enhanced susceptibility of HBV-infected
hepatocytes to cytolytic T cells, and pro-apoptotic pathway.
Expression of HbxAg and its antibodies associated with
enhanced HBV DNA replication has been implicated in Figure 21.8 Sequence of serologic and viral markers in acute
hepatocelluar carcinoma in patients of chronic hepatitis. hepatitis B.
PATHOGENESIS. The evidence linking immuno- to anti-HBe during acute stage of illness is a prognostic sign
pathogenetic mechanism with hepatocellular damage is for resolution of infection.
much stronger in HBV infection than with HAV infection.
In support of immune pathogenesis is the demonstration of 5. HBcAg. HBcAg derived from core protein cannot be
several immunological markers (serologic as well as viral), detected in the blood. But HBcAg can be demonstrated in
and molecular and morphologic evidence that hepatocytic the nuclei of hepatocytes in carrier state and in chronic
damage is initiated by virus-infected CD8+T cytotoxic cells. hepatitis patients by Orcein staining but not in the liver cells
during acute stage.
Serologic and viral markers. Various immunological markers CHAPTER 21
indicative of presence of HBV infection can be demonstrated 6. Anti-HBc. Antibody to HBcAg called anti-HBc can,
in the sera as well as in the hepatocytes of infected however, be detected in the serum of acute hepatitis B
individuals. These are as under (Fig. 21.8): patients during pre-icteric stage. Anti-HBc may be IgM or
IgG class antibody. IgM anti-HBc persists for 4-6 months and
1. HBsAg. In 1965, Blumberg and colleagues in Philadelphia is followed later by IgG anti-HBc. Thus detection of high titre
found a lipoprotein complex in the serum of a multiple- of IgM anti-HBc is indicative of recent acute HBV infection,
transfused haemophiliac of Australian aborigine which was while elevated level of IgG anti-HBc suggests HBV infection
subsequently shown by them to be associated with serum in the remote past.
hepatitis. This antigen was termed Australia antigen by them 7. HBV-DNA. Detection of HBV-DNA by molecular
(In 1977, Blumberg was awarded the Nobel prize for his hybridisation using the Southern blot technique is the most
discovery). The term Australia antigen is now used sensitive index of hepatitis B infection. It is present in pre-
synonymous with hepatitis B surface antigen (HBsAg). symptomatic phase and transiently during early acute stage.
HBsAg appears early in the blood after about 6 weeks of
infection and its detection is an indicator of active HBV Hepatitis D
infection. It usually disappears in 3-6 months. Its persistence
for more than 6 months implies a carrier state. HBsAg may Infection with delta virus (HDV) in the hepatocyte nuclei of The Liver, Biliary Tract and Exocrine Pancreas
also be demonstrated in the cell membrane of hepatocytes HBsAg-positive patients is termed hepatitis D. HDV is a
of carriers and chronic hepatitis patients by Orcein staining defective virus for which HBV is the helper. Thus, hepatitis
(orange positivity) but not in the hepatocytes during acute D develops when there is concomitant hepatitis B infection.
stage of illness. HDV infection and hepatitis B may be simultaneous (co-
infection), or HDV may infect a chronic HBsAg carrier
2. Anti-HBs. Specific antibody to HBsAg in serum called
anti-HBs appears late, about 3 months after the onset. Anti- (superinfection) (Fig. 21.9):
HBs response may be both IgM and IgG type. The prevalence With coinfection, acute hepatitis D may range from mild
rate of anti-HBs ranges from 10-15%. In these individuals it to fulminant hepatitis but fulminant hepatitis is more likely
persists for life providing protection against reinfection with in such simultaneous delta infection. Chronicity rarely
HBV. develops in coinfection.
With superinfection (incubation period 30-35 days),
3. HBeAg. HBeAg derived from core protein is present chronic HBV infection gets worsened indicated by
transiently (3-6 weeks) during an acute attack. Its persistence appearance of severe and fulminant acute attacks,
beyond 10 weeks is indicative of development of chronic liver progression of carrier stage to chronic delta hepatitis or
disease and carrier state.
acceleration towards cirrhosis. Occurrence of hepatocellular
4. Anti-HBe. Antibody to HBeAg called anti-HBe appears carcinoma is, however, less common in HBsAg carriers with
after disappearance of HBeAg. Seroconversion from HBeAg HDV infection.
608
Figure 21.9 Consequences of coinfection versus superinfection in combined HDV-HBV infection.
HDV infection is worldwide in distribution though the accidental cuts and needle-pricks in health workers. About
incidence may vary in different countries. Endemic regions 90% of post-transfusion hepatitis is of hepatitis C type. About
are Southern Europe, Middle-East, South India and parts of 1-2% of volunteer blood donors and up to 5% of professional
Africa. The high-risk individuals for HDV infection are the blood donors are carriers of HCV. Hepatitis C has an
same as for HBV infection i.e. intravenous drug abusers, incubation period of 20-90 days (mean 50 days). Clinically,
homosexuals, transfusion recipients, and health care acute HCV hepatitis is milder than HBV hepatitis but HCV
workers. has a higher rate of progression to chronic hepatitis than
HBV. Persistence of infection and chronic hepatitis are the
SECTION III
HEPATITIS DELTA VIRUS (HDV). The etiologic agent, key features of HCV. Occurrence of cirrhosis after 5 to 10
HDV, is a small single-stranded RNA particle with a years and progression to hepatocellular carcinoma are other
diameter of 36 nm. It is double-shelled—the outer shell late consequences of HCV infection. Currently, HCV is
consists of HBsAg and the inner shell consists of delta antigen considered more important cause of chronic liver disease
provided by a circular RNA strand. It is highly infectious worldwide than HBV.
and can induce hepatitis in any HBsAg-positive host. HDV
replication and proliferation takes place within the nuclei of HEPATITIS C VIRUS (HCV). HCV is a single-stranded,
liver cells. Markers for HDV infection include the following: enveloped RNA virus, having a diameter of 30-60 nm. HCV
1. HDV identification in the blood and in the liver cell nuclei. genome has about 3000 amino acids. The genomic
2. HDAg detectable in the blood and on fixed liver tissue organisation of HCV shows a 5’ terminal end, C (capsid)
specimens. region and the envelope regions E1 and E2 in the exons
Systemic Pathology
(Fig. 21.10).
3. Anti-HD antibody in acute hepatitis which is initially IgM The viral proteins result in corresponding serologic and
type and later replaced by IgG type anti-HD antibody which virologic markers for HCV infection as under (Fig. 21.11):
persists for life to confer immunity against reinfection.
1. Anti-HCV antibodies. Three generations of anti-HCV IgG
PATHOGENESIS. HDV, unlike HBV, is thought to cause assays are available:
direct cytopathic effect on hepatocytes. However, there are i) First generation antibodies are against C100-3 region
examples of transmission of HDV infection from individuals proteins and appear 1 to 3 months after infection.
who themselves have not suffered from any attack of
hepatitis, suggesting that it may not be always cytopathic.
Thus, the exact mechanism remains unresolved.
Hepatitis C
The diagnosis of a third major category of hepatitis was
earlier made after exclusion of infection with other known
hepatitis viruses and was initially designated non-A, non-B
(NANB) hepatitis. However, now this third type has been
characterised and is called hepatitis C.
Hepatitis C infection is acquired by blood transfusions,
blood products, haemodialysis, parenteral drug abuse and Figure 21.10 Diagrammatic structure of hepatitis C virus.
isolated from stools, bile and liver of infected persons. 609
Serologic markers for HEV include the following:
1. Anti-HEV antibodies of both IgM and IgG class.
2. HEV-RNA.
However, testing for these markers for HEV is currently
not available.
Hepatitis G
A virus distinct from the foregoing hepatitis viruses has been
designated separately as hepatitis G (HGV). HGV infection
has been found in blood donors, patients on haemodialysis
and as coinfection with HIV. However, unlike HCV, HGV is
cleared from the plasma in majority of individuals while a
small percentage of cases have chronic HGV infection who
do not develop hepatitis, nor does infected blood require
Figure 21.11 Sequence of serologic and viral markers of HCV screening for HGV RNA.
infection.
HEPATITIS G VIRUS (HGV). HGV is a single-stranded
ii) Second generation antibodies are against C200 and C33c RNA virus. The virus has been identified by PCR ampli-
proteins and appear about one month earlier than the fication technique.
first generation.
iii) Third generation antibodies are against C22-3 and NS-5 CLINICOPATHOLOGIC SPECTRUM
region proteins and are detected even earlier. Among the various etiologic types of hepatitis, evidence
2. HCV-RNA. HCV infection is, however, confirmed by linking HBV and HCV infection with the spectrum of clinico-
HCV-RNA employing PCR technique which can be detected pathologic changes is stronger than with other hepatotropic CHAPTER 21
within a few days after exposure to HCV infection, much viruses. The typical pathologic changes of hepatitis by major
before appearance of anti-HCV and persists for the duration hepatotropic viruses are virtually similar. HAV and HEV,
of HCV infection. however, do not have a carrier stage nor cause chronic
hepatitis. The various clinical patterns and pathologic
PATHOGENESIS. Cell-mediated immune mechanism and consequences of different hepatotropic viruses can be
production of antiviral cytokines by T-lymphocytes certainly considered under the following headings:
play a role in hepatocytic injury due to HCV. HCV virions i) Carrier state
have not been identified in hepatocytes. Perhaps, HCV ii) Asymptomatic infection
infection of lymphoid cells may induce immunologic injury iii) Acute hepatitis
to hepatocytes. In patients with chronic HCV hepatitis, HCV- iv) Chronic hepatitis
specific CD4+ T cells and HLA-restricted CD8+ T cells have v) Fulminant hepatitis (Submassive to massive necrosis)
been identified. Crossreactivity between viral antigens and In addition, progression to cirrhosis (page 624) and
host autoantibodies to liver-kidney microsomal antigen (anti- association with hepatocellular carcinoma (page 634) are
LKM) have been reported in a subset of patients that explains known to occur in certain types of hepatitis which are
the association of autoimmune hepatitis and HCV hepatitis. discussed separately later. The Liver, Biliary Tract and Exocrine Pancreas
Hepatitis E I. Carrier State
Hepatitis E is an enterically-transmitted virus, previously An asymptomatic individual without manifest disease,
labelled as epidemic or enterically transmitted variant of non- harbouring infection with hepatotropic virus and capable of
A non-B hepatitis. The infection occurs in young or middle- transmitting it is called carrier state. There can be 2 types of
aged individuals, primarily seen in India, other Asian carriers:
countries, Africa and central America. 1. An ‘asymptomatic healthy carrier’ who does not suffer from
The infection is generally acquired by contamination of ill-effects of the virus infection but is capable of transmitting.
water supplies such as after monsoon flooding. However,
compared with HAV, secondary person-to-person infection 2. An ‘asymptomatic carrier with chronic disease’ capable of
does not occur with HEV. Thus HEV has some common transmitting the organisms.
epidemiologic features with HAV. HEV infection has a As stated before, hepatitis A and E do not produce the
particularly high mortality in pregnant women but is carrier state. Hepatitis B is responsible for the largest number
otherwise a self-limited disease and has not been associated of carriers in the world, while concomitant infection with
with chronic liver disease. HDV more often causes progressive disease rather than an
asymptomatic carrier state. There is geographic variation in
HEPATITIS E VIRUS (HEV). HEV is a single-stranded 32- incidence of HBV carrier state: while in normal population
34 nm, icosahedral non-enveloped virus. The virus has been in US and western Europe it is less than 0.5%, its prevalence
610
Figure 21.12 Acute viral hepatitis. The predominant histologic changes are: variable degree of necrosis of hepatocytes, most marked in zone
3 (centrilobular); and mononuclear cellular infiltrate in the lobule. Mild degree of liver cell necrosis is seen as ballooning degeneration while
acidophilic Councilman bodies (inbox) are indicative of more severe liver cell injury.
is much higher in Asian and tropical countries (5-20%). An 1. Incubation period: It varies among different hepatotropic
estimated 2-3% of the general population are asymptomatic viruses: for hepatitis A it is about 4 weeks (15-45 days); for
carriers of HCV. Data on HBV carrier state reveal role of 2 hepatitis B the average is 10 weeks (30-180 days); for hepatitis
important factors rendering the individual more vulnerable D about 6 weeks (30-50 days); for hepatitis C the mean
to harbour the organisms—early age at infection and impaired incubation period is about 7 weeks (20-90 days), and for
immunity. Whereas approximately 10% of adults contracting hepatitis E it is 2-8 weeks (15-60 days). The patient remains
hepatitis B infection develop carrier state, 90% of infected asymptomatic during incubation period but the infectivity
neonates fail to clear HBsAg from the serum within 6 months is highest during the last days of incubation period.
SECTION III
and become HBV carriers. 2. Pre-icteric phase: This phase is marked by prodromal
Clinical recognition of carrier state of HBV is more constitutional symptoms that include anorexia, nausea,
frequently done by detection of HBsAg in the serum and less vomiting, fatigue, malaise, distaste for smoking, arthralgia
often by other markers such as HBeAg, HBcAg and and headache. There may be low-grade fever preceding the
antibodies. Concomitant infection of HDV with HBV onset of jaundice, especially in hepatitis A. The earliest
depends upon the demonstration of anti-HD. laboratory evidence of hepatocellular injury in pre-icteric
phase is the elevation of transaminases.
MORPHOLOGIC FEATURES. Carriers of HBV may or 3. Icteric phase: The prodromal period is heralded by the
may not show changes on liver biopsy. onset of clinical jaundice and the constitutional symptoms
Healthy HBV carriers may show no changes or minor diminish. Other features include dark-coloured urine due to
hepatic change such as presence of finely granular, bilirubinuria, clay-coloured stools due to cholestasis, pruritus
Systemic Pathology
ground-glass, eosinophilic cytoplasm as evidence of as a result of elevated serum bile acids, loss of weight and
HBsAg. abdominal discomfort due to enlarged, tender liver. The
Asymptomatic carriers with chronic disease may show diagnosis is based on deranged liver function tests (e.g.
changes of chronic hepatitis and even cirrhosis. elevated levels of serum bilirubin, transaminases and
alkaline phosphatase; prolonged prothrombin time and
II. Asymptomatic Infection hyperglobulinaemia) and serologic detection of hepatitis
These are cases who are detected incidentally to have antigens and antibodies.
infection with one of the hepatitis viruses as revealed by their 4. Post-icteric phase: The icteric phase lasting for about 1
raised serum transaminases or by detection of the presence to 4 weeks is usually followed by clinical and biochemical
of antibodies but are otherwise asymptomatic. recovery in 2 to 12 weeks. The recovery phase is more
prolonged in hepatitis B and hepatitis C. Up to 1% cases of
III. Acute Hepatitis acute hepatitis may develop severe form of the disease
The most common consequence of all hepatotropic viruses (fulminant hepatitis); and 5-10% of cases progress on to
is acute inflammatory involvement of the entire liver. In chronic hepatitis. Evolution into the carrier state (except in
general, type A, B, C, D and E run similar clinical course HAV and HEV infection) has already been described above.
and show identical pathologic findings. MORPHOLOGIC FEATURES. Grossly, the liver is
Clinically, acute hepatitis is categorised into 4 phases:
incubation period, pre-icteric phase, icteric phase and post- slightly enlarged, soft and greenish.
Histologically, the changes are as follows (Fig. 21.12):
icteric phase.
1. Hepatocellular injury: There may be variation in the and hepatitis D infection. However, some non-viral causes 611
degree of liver cell injury but it is most marked in zone 3 of chronic hepatitis include: Wilson’s disease, α-1-antitrypsin
(centrilobular zone): deficiency, chronic alcoholism, drug-induced injury and
i) Mildly injured hepatocytes appear swollen with autoimmune diseases. The last named gives rise to
granular cytoplasm which tends to condense around the autoimmune or lupoid hepatitis which is characterised by
nucleus (ballooning degeneration). positive serum autoantibodies (e.g. antinuclear, anti-smooth
muscle and anti-mitochondrial) and a positive LE cell test
ii) Others show acidophilic degeneration in which the but negative for serologic markers of viral hepatitis.
cytoplasm becomes intensely eosinophilic, the nucleus Until recent years, prediction of prognosis of chronic
becomes small and pyknotic and is eventually extruded hepatitis used to be made on the basis of morphology which
from the cell, leaving behind necrotic, acidophilic mass
called Councilman body or acidophil body by the process divided it into 2 main types—chronic persistent and chronic
known as apoptosis. active (aggressive) hepatitis. A third form, chronic lobular
hepatitis is distinguished separately by some as mild form of
iii) Another type of hepatocellular necrosis is dropout lobular inflammation without inflammation of portal tracts
necrosis in which isolated or small clusters of hepatocytes but these cases often recover completely. However,
undergo lysis. subsequent studies have revealed that morphologic subtypes
iv) Bridging necrosis is a more severe form of hepato- do not necessarily correlate with prognosis since the disease
cellular injury in acute viral hepatitis and may progress is not essentially static but may vary from mild form to severe
to fulminant hepatitis or chronic hepatitis (discussed and vice versa. Besides, two other factors which determine
below). Bridging necrosis is characterised by bands of the vulnerability of a patient of viral hepatitis to develop
necrosis linking portal tracts to central hepatic veins, one chronic hepatitis are: impaired immunity and extremes of age
central hepatic vein to another, or a portal tract to another at which the infection is first contracted. Currently, therefore,
tract. chronic hepatitis is classified on the basis of etiology and
2. Inflammatory infiltrate: There is infiltration by hepatitis activity score (described below). The frequency and
mononuclear inflammatory cells, usually in the portal severity with which hepatotropic viruses cause chronic
tracts, but may permeate into the lobules. hepatitis varies with the organisms as under: CHAPTER 21
3. Kupffer cell hyperplasia: There is reactive hyper- HCV infection accounts for 40-60% cases of chronicity in
plasia of Kupffer cells many of which contain phago- adults. HCV infection is particularly associated with
cytosed cellular debris, bile pigment and lipofuscin progressive form of chronic hepatitis that may evolve into
granules. cirrhosis.
4. Cholestasis: Biliary stasis is usually not severe in viral HBV causes chronic hepatitis in 90% of infected infants
hepatitis and may be present as intracytoplasmic bile and in about 5% adult cases of hepatitis B.
pigment granules. HDV superinfection on HBV carrier state may be
5. Regeneration: As a result of necrosis of hepatocytes, responsible for chronic hepatitis in 10-40% cases.
there is lobular disarray. Surviving adjacent hepatocytes HAV and HEV do not produce chronic hepatitis.
undergo regeneration and hyperplasia. If the necrosis
causes collapse of reticulin framework of the lobule, MORPHOLOGIC FEATURES. The pathologic features
healing by fibrosis follows, distorting the lobular are common to both HBV and HCV infection and include
architecture. the following lesions (Fig. 21.13).
1. Piecemeal necrosis. Piecemeal necrosis is defined as
The above histologic changes apply to viral hepatitis by periportal destruction of hepatocytes at the limiting plate
various types of hepatotropic viruses in general, and by HBV (piecemeal = piece by piece). Its features in chronic hepatitis The Liver, Biliary Tract and Exocrine Pancreas
in particular. It is usually not possible to distinguish are as under:
histologically between viral hepatitis of various etiologies, i) Necrosed hepatocytes at the limiting plate in
but the following morphologic features may help in giving periportal zone.
an etiologic clue: ii) Interface hepatitis due to expanded portal tract by
HAV hepatitis is a panlobular involvement by heavy infiltration of lymphocytes, plasma cells and
inflammatory infiltrate compared to other types. macrophages.
HCV hepatitis causes milder necrosis, with fatty change iii) Expanded portal tracts are often associated with
in hepatocytes, presence of lymphoid aggregates in the portal proliferating bile ductules as a response to liver cell injury.
triads and degeneration of bile duct epithelium.
2. Portal tract lesions. All forms of chronic hepatitis are
IV. Chronic Hepatitis characterised by variable degree of changes in the portal
tract.
Chronic hepatitis is defined as continuing or relapsing i) Inflammatory cell infiltration by lymphocytes, plasma
hepatic disease for more than 6 months with symptoms along cells and macrophages (triaditis).
with biochemical, serologic and histopathologic evidence of ii) Proliferated bile ductules in the expanded portal tracts.
inflammation and necrosis. Majority of cases of chronic iii) Additionally, chronic hepatitis C may show lymphoid
hepatitis are the result of infection with hepatotropic aggregates or follicles with reactive germinal centre and
viruses—hepatitis B, hepatitis C and combined hepatitis B
612
SECTION III
Figure 21.13 Chronic hepatitis. Diagrammatic representation of
pathologic changes in chronic hepatitis (B) contrasted with normal
morphology (A). Photomicrograph on right (C) shows stellate-shaped
portal triad, with extension of fibrous spurs into lobules. The portal tract
is expanded due to increased lymphomononuclear inflammatory cells
which are seen to breach the limiting plate (i.e. hepatocytes at the interface
of portal tract and lobule are destroyed).
infiltration of inflammatory cells in the damaged bile duct i) At first, there is periportal fibrosis at the sites of inter-
epithelial cells. face hepatitis giving the portal tract stellate-shaped
3. Intralobular lesions. Generally, the architecture of appearance.
Systemic Pathology
lobule is retained in mild to moderate chronic hepatitis. ii) Progressive cases show bridging fibrosis connecting
i) There are focal areas of necrosis and inflammation portal tract-to-portal tract or portal tract-to-central vein
within the hepatic parenchyma. traversing the lobule.
ii) Scattered acidophilic bodies in the lobule. iii) End-stage of chronic hepatitis is characterised by dense
iii) Kupffer cell hyperplasia. collagenous septa destroying lobular architecture and
iv) More severe form of injury shows bridging necrosis forming nodules resulting in postnecrotic cirrhosis.
(i.e. bands of necrosed hepatocytes that may bridge portal
tract-to-central vein, central vein-to-central vein, and As prognostic indicator of chronic hepatitis, criteria have
portal tract-to-portal tract). been evolved to classify chronic hepatitis by giving hepatitis
v) Regenerative changes in hepatocytes in cases of activity score (ranging from none to minimal/mild to
persistent hepatocellular necrosis. moderate and severe) described by Knodell and Ishak based
vi) Cases of chronic hepatitis C show moderate fatty on the following features:
change.
vii) Cases of chronic hepatitis B show scattered ground- A. Necroinflammatory activity:
glass hepatocytes indicative of abundance of HBsAg in Periportal necrosis i.e. piecemeal necrosis and/ or bridging
the cytoplasm. necrosis (ranging from score 0 as ‘no necrosis’ to score 4 as
‘multilobular necrosis’).
4. Bridging fibrosis. The onset of fibrosis in chronic Intralobular necrosis, focal or confluent (ranging from score
hepatitis from the area of interface hepatitis and bridging 0 as ‘none’ to score 4 for ‘>10 foci’ for focal necrosis, and
necrosis is a feature of irreversible damage.
score 6 as ‘panacinar/multiacinar’ for confluent necrosis).
Extent and depth of portal inflammation (ranging from grade necrosis in which the liver failure is rapid and fulminant 613
0 as ‘no inflammation’ to grade 4 having ‘marked portal occurring in 2-3 weeks.
inflammation’). Fulminant hepatitis of either of the two varieties can occur
from viral and non-viral etiologies:
B. Stage of fibrosis:
Extent and density of fibrosis (ranging from score 0 as ‘no Acute viral hepatitis accounts for about half the cases, most
fibrosis’ to score 6 as ‘cirrhosis’). often from HBV and HCV; less frequently from combined
HBV-HDV and rarely from HAV. However, HEV infection
CLINICAL FEATURES. The clinical features of chronic is a serious complication in pregnant women. In addition,
hepatitis are quite variable ranging from mild disease to full- herpesvirus can also cause serious viral hepatitis.
blown picture of cirrhosis. Non-viral causes include acute hepatitis due to drug
i) Mild chronic hepatitis shows only slight but persistent toxicity (e.g. acetaminophen, non-steroidal anti-
elevation of transaminases (‘transaminitis’) with fatigue, inflammatory drugs, isoniazid, halothane and anti-
malaise and loss of appetite. depressants), poisonings, hypoxic injury and massive
ii) Other cases may show mild hepatomegaly, hepatic infiltration of malignant tumours into the liver.
tenderness and mild splenomegaly. The patients present with features of hepatic failure with
hepatic encephalopathy (page 602). The mortality rate is high
iii) Laboratory findings may reveal prolonged prothrombin if hepatic transplantation is not undertaken.
time, hyperbilirubinaemia, hyperglobulinaemia and
markedly elevated alkaline phosphatase.
MORPHOLOGIC FEATURES. Grossly, the liver is small
iv) Systemic features of circulating immune complexes due and shrunken, often weighing 500-700 gm. The capsule
to HBV and HCV infection may produce features of immune is loose and wrinkled. The sectioned surface shows diffuse
complex vasculitis, glomerulonephritis and cryoglobuli- or random involvement of hepatic lobes. There are
naemia in a proportion of cases. extensive areas of muddy-red and yellow necrosis
However, clinical features do not correlate with morpho- (previously called acute yellow atrophy) and patches of
logic appearance of the liver biopsy. Some patients may have green bile staining.
mild form of disease without progressing for several years Histologically, two forms of fulminant necrosis are CHAPTER 21
while others may show rapid evolution into cirrhosis with distinguished—submassive and massive necrosis
its complications over a period of few years. Patients of long- (Fig. 21.14).
standing HBV and HCV chronic infection are known to i) In submassive necrosis, large groups of hepatocytes
evolve into hepatocellular carcinoma. in zone 3 (centrilobular area) and zone 2 (mid zone) are
wiped out leading to a collapsed reticulin framework.
V. Fulminant Hepatitis Regeneration in submassive necrosis is more orderly and
(Submassive to Massive Necrosis) may result in restoration of normal architecture.
Fulminant hepatitis is the most severe form of acute hepatitis ii) In massive necrosis, the entire liver lobules are
in which there is rapidly progressive hepatocellular failure. necrotic. As a result of loss of hepatic parenchyma, all that
Two patterns are recognised—submassive necrosis having a is left is the collapsed and condensed reticulin framework
less rapid course extending up to 3 months; and massive and portal tracts with proliferated bile ductules plugged The Liver, Biliary Tract and Exocrine Pancreas
Figure 21.14 Fulminant hepatitis. There is wiping out of liver lobules with only collapsed reticulin framework left out in their place, highlighted
by reticulin stain (right photomicrograph). There is no significant inflammation or fibrosis.
614 3. Hepatitis D. Hepatitis D infection can also be prevented
by hepatitis B vaccine.
4. Hepatitis C. Currently, hepatitis C vaccine has yet not
been feasible though antibodies to HCV envelope have been
developed.
5. Hepatitis E. It is not certain whether immune globulin
(like for HAV) prevents hepatitis E infection or not but a
vaccine against HEV is yet to be developed.
OTHER INFECTIONS AND INFESTATIONS
Apart from viral hepatitis, the liver is affected by infections
with bacteria, spirochaetes and fungi and is involved in some
parasitic infestations. Some common examples of such
conditions are described below.
Figure 21.15 Clinicopathologic course of HBV and HCV infection.
CHOLANGITIS
with bile. Inflammatory infiltrate is scanty. Regeneration, Cholangitis is the term used to describe inflammation of the
if it takes place, is disorderly forming irregular masses of extrahepatic or intrahepatic bile ducts, or both. There are two
hepatocytes. Fibrosis is generally not a feature of main types of cholangitis—pyogenic and primary sclerosing.
fulminant hepatitis. While primary sclerosing cholangitis is discussed later with
biliary cirrhosis (page 625), pyogenic cholangitis is described
The clinicopathologic course in two major forms of below.
hepatitis, HBV and HCV, is summarised in Fig. 21.15.
Pyogenic Cholangitis
IMMUNOPROPHYLAXIS AND HEPATITIS VACCINES
Cholangitis occurring secondary to obstruction of a major
Best prophylaxis against the viral hepatitis remains extrahepatic duct causes pyogenic cholangitis. Most
prevention of its spread to the contacts after detection and commonly, the obstruction is from impacted gallstone; other
SECTION III
identification of route by which infection is acquired such as causes are carcinoma arising in the extrahepatic ducts,
from food or water contamination, sexual spread or carcinoma head of pancreas, acute pancreatitis and
parenteral spread. Of late, however, immunoprophylaxis and inflammatory strictures in the bile duct. Bacteria gain entry
a few hepatitis vaccines have been developed and some more to the obstructed duct and proliferate in the bile. Infection
are under development. The principle underlying either of spreads along the branches of obstructed duct and reaches
these two forms of prophylaxis is that the persons who the liver, termed ascending cholangitis. The common infecting
develop good antibody response to the antigen of the bacteria are enteric organisms such as E.coli, Klebsiella and
hepatotropic virus following active infection are protected Enterobacter.
against the disease on reinfection. Thus, pre-testing of
persons may be carried out so as to determine their antibody MORPHOLOGIC FEATURES. The affected ducts show
Systemic Pathology
level. Immunoprophylaxis and hepatitis vaccination are small beaded abscesses accompanied by bile stasis along
unnecessary if the pre-testing for antibodies is positive. their course and larger abscesses within the liver. The
1. Hepatitis A. Passive immunisation with immune abscesses are composed of acute inflammatory cells which
globulin as well as active immunisation with a killed vaccine in time are replaced by chronic inflammatory cells and
are available. enclosed by fibrous capsule.
2. Hepatitis B. Earlier, only passive immunoprophylaxis
with standard immune globulin was used. Later, active PYOGENIC LIVER ABSCESS
immunisation against HBsAg was introduced. Current Most liver abscesses are of bacterial (pyogenic) origin; less
recommendations include pre-exposure and post-exposure often they are amoebic, hydatid and rarely actinomycotic.
prophylaxis with recombinant hepatitis B vaccine:
Pyogenic liver abscesses have become uncommon due to
Pre-exposure prophylaxis is done for individuals at high- improved diagnostic facilities and the early use of antibiotics.
risk e.g. health care workers, haemodialysis patients and However, their incidence is higher in old age and in
staff, haemophiliacs, intravenous drug users etc. Three immunosuppressed patients such as in AIDS, transplant
intramuscular injections of hepatitis vaccine at 0, 1 and 6 recipients and those on intensive chemotherapy.
months are recommended. Pyogenic liver abscesses are classified on the basis of the
Post-exposure prophylaxis is carried out for unvaccinated mode of entry as under:
persons exposed to HBV infection and includes prophylaxis 1. Ascending cholangitis through ascending infection in the
with combination of hepatitis B immune globulin and biliary tract due to obstruction e.g. gallstones, cancer,
hepatitis B vaccine. sclerosing cholangitis and biliary strictures.
by the spread of Entamoeba histolytica from intestinal lesions. 615
The trophozoite form of amoebae in the colon invade the
colonic mucosa forming flask-shaped ulcers from where they
are carried to the liver in the portal venous system (page
188) . Amoebae multiply and block small intrahepatic portal
radicles resulting in infarction necrosis of the adjacent liver
parenchyma.
The patients, generally from tropical and subtropical
countries, may give history of amoebic dysentery in the past.
Cysts of E. histolytica in stools are present in only 15% of
patients of hepatic amoebiasis. Intermittent low-grade fever,
pain and tenderness in the liver area are common presenting
features. A positive haemagglutination test is quite sensitive
and useful for diagnosis of amoebic liver abscess.
Figure 21.16 Gross appearance of pyogenic abscesses in the liver.
MORPHOLOGIC FEATURES. Grossly, amoebic liver
abscesses are usually solitary and more often located in
2. Portal pyaemia by means of spread of pelvic or gastro-
intestinal infection resulting in portal pylephlebitis or septic the right lobe in the posterosuperior portion. Amoebic
emboli e.g. from appendicitis, empyema of gallbladder, liver abscess may vary greatly in size but is generally of
diverticulitis, regional enteritis, pancreatitis, infected the size of an orange. The centre of the abscess contains
haemorrhoids and neonatal umbilical vein sepsis. large necrotic area having reddish-brown, thick pus
3. Septicaemia through spread by hepatic artery. resembling anchovy or chocolate sauce. The abscess wall
4. Direct infection resulting in solitary liver abscess e.g. from consists of irregular shreds of necrotic liver tissue (Fig.
adjacent perinephric abscess, secondary infection in amoebic 21.17).
liver abscess, metastasis and formation of haematoma Histologically, the necrotic area consists of degenerated
following trauma. liver cells, leucocytes, red blood cells, strands of CHAPTER 21
5. Iatrogenic causes include liver biopsy, percutaneous biliary connective tissue and debris. Amoebae are most easily
drainage and accidental surgical trauma. found in the liver tissue at the margin of abscess. PAS-
6. Cryptogenic from unknown causes, especially in the staining is employed to confirm the trophozoites of E.
elderly. histolytica.
The commonest infecting organisms are gram-negative
bacteria chiefly E. coli; others are Pseudomonas, Klebsiella, HEPATIC TUBERCULOSIS
Enterobacter and a number of anaerobic organisms, Tuberculosis of the liver occurs as a result of miliary
bacteroides and actinomyces. dissemination from primary complex or from chronic adult
Liver abscesses are clinically characterised by pain in the pulmonary tuberculosis. The diagnosis is possible by liver
right upper quadrant, fever, tender hepatomegaly and biopsy. The patients may have unexplained fever, jaundice,
sometimes jaundice. Laboratory examination reveals hepatomegaly or hepatosplenomegaly. There may be
leucocytosis, elevated serum alkaline phosphatase, elevated serum alkaline phosphatase levels and
hypoalbuminaemia and a positive blood culture. hyperglobulinaemia.
MORPHOLOGIC FEATURES. Grossly depending upon MORPHOLOGIC FEATURES. The basic lesion is the
the cause for pyogenic liver abscess, they occur as single epithelioid cell granuloma characterised by central The Liver, Biliary Tract and Exocrine Pancreas
or multiple yellow abscesses, 1 cm or more in diameter,
in an enlarged liver. A single abscess generally has a thick
fibrous capsule. The abscesses are particularly common
in right lobe of the liver (Fig. 21.16).
Microscopically, typical features of abscess are seen.
There are multiple small neutrophilic abscesses with areas
of extensive necrosis of the affected liver parenchyma. The
adjacent viable area shows pus and blood clots in the
portal vein, inflammation, congestion and proliferating
fibroblasts. Direct extension from the liver may lead to
subphrenic or pleuro-pulmonary suppuration or
peritonitis. There may be small pyaemic abscesses
elsewhere such as in the lungs, kidneys, brain and spleen.
AMOEBIC LIVER ABSCESS
Amoebic liver abscesses are less common than pyogenic liver Figure 21.17 Amoebic liver abscess is commonly solitary and its
abscesses and have many similar features. They are caused wall is irregular and necrotic.
616 HYDATID DISEASE (ECHINOCOCCOSIS)
Hydatid disease occurs as a result of infection by the larval
cyst stage of the tapeworm, Echinococcus granulosus. The dog
is the common definite host, while man, sheep and cattle
are the intermediate hosts. The dog is infected by eating the
viscera of sheep containing hydatid cysts. The infected faeces
of the dog contaminate grass and farmland from where the
ova are ingested by sheep, pigs and man. Thus, man can
acquire infection by handling dogs as well as by eating conta-
minated vegetables. The ova ingested by man are liberated
from the chitinous wall by gastric juice and pass through
the intestinal mucosa from where they are carried to the liver
by portal venous system. These are trapped in the hepatic
sinusoids where they eventually develop into hydatid cyst.
About 70% of hydatid cysts develop in the liver which acts
as the first filter for ova. However, ova which pass through
the liver enter the right side of the heart and are caught in
the pulmonary capillary bed and form pulmonary hydatid
cysts. Some ova which enter the systemic circulation give
Figure 21.18 Miliary tuberculosis liver. The hepatic parenchyma
shows epithelioid granulomas with small areas of central necrosis and rise to hydatid cysts in the brain, spleen, bone and muscles.
surrounded peripherally by Langhans’ giant cells and lymphocytes. The disease is common in sheep-raising countries such
as Australia, New Zealand and South America. The
uncomplicated hydatid cyst of the liver may be silent or may
caseation necrosis with destruction of the reticulin produce dull ache in the liver area and some abdominal
framework and peripheral cuff of lymphocytes distension.
(Fig. 21.18). Ziehl-Neelsen staining for AFB or culture of Complications of hydatid cyst include its rupture (e.g. into
the organism from the biopsy tissue is confirmatory. Rare the peritoneal cavity, bile ducts and lungs), secondary
lesions consist of tuberculous cholangitis and tuberculous infection and hydatid allergy due to sensitisation of the host
pylephlebitis. with cyst fluid. The diagnosis is made by peripheral blood
SECTION III
eosinophilia, radiologic examination and serologic tests such
as indirect haemagglutination test and Casoni skin test.
Systemic Pathology
Figure 21.19 Hydatid cyst in the liver. The cyst wall is composed of
whitish membrane resembling the membrane of a hard boiled egg.
617
Figure 21.20 Microscopy shows three layers in the wall of hydatid cyst. Inbox in the right photomicrograph shows a scolex with a row of
hooklets.
MORPHOLOGIC FEATURES. Hydatid cyst grows predispose an individual to hepatic drug injury such as pre-
slowly and may eventually attain a size over 10 cm in existing liver disease, aging, female sex and genetic inability
diameter in about 5 years. E. granulosus generally causes to perform a particular biotransformation.
unilocular hydatid cyst while E. multilocularis results in HEPATOTOXICITY. Toxic liver injury produced by drugs
multilocular or alveolar hydatid disease in the liver. and chemicals may virtually mimic any form of naturally-
The cyst wall is composed of 3 distinguishable zones— occurring liver disease. In fact, any patient presenting with CHAPTER 21
outer pericyst, intermediate characteristic ectocyst and inner liver disease or unexplained jaundice is thoroughly
endocyst (Fig. 21.19): questioned about history of drug intake or exposure to
1. Pericyst is the outer host inflammatory reaction chemicals. Hepatotoxicity from drugs and chemicals is the
consisting of fibroblastic proliferation, mononuclear cells, commonest form of iatrogenic disease. Severity of
eosinophils and giant cells, eventually developing into hepatotoxicity is greatly increased if the drug is continued
dense fibrous capsule which may even calcify. after symptoms develop.
2. Ectocyst is the intermediate layer composed of Among the various inorganic compounds producing
characteristic acellular, chitinous, laminated hyaline hepatotoxicity are arsenic, phosphorus, copper and iron.
material (Fig. 21.20). Organic agents include certain naturally-occurring plant
3. Endocyst is the inner germinal layer bearing daughter toxins such as pyrrolizidine alkaloids, mycotoxins and
cysts (brood-capsules) and scolices projecting into the bacterial toxins. The synthetic group of organic compounds
lumen. are a large number of medicinal agents. In addition, exposure
Hydatid sand is the grain-like material composed of to hepatotoxic compounds may be occupational,
numerous scolices present in the hydatid fluid. Hydatid environmental or domestic that could be accidental,
fluid, in addition, contains antigenic proteins so that its homicidal or suicidal ingestion. The Liver, Biliary Tract and Exocrine Pancreas
liberation into circulation gives rise to pronounced In general, drug reactions affecting the liver are divided
eosinophilia or may cause anaphylaxis. into two main classes:
1. Direct or predictable, when the drug or one of its
CHEMICAL AND DRUG INJURY metabolites is either directly toxic to the liver or it lowers
the host immune defense mechanism. The adverse effects
HEPATIC DRUG METABOLISM. The liver plays a central occur in most individuals who consume them and their
role in the metabolism of a large number of organic and hepatotoxicity is dose-dependent e.g. carbon tetrachloride.
inorganic chemicals and drugs which gain access to the body
by inhalation, injection, or most commonly, via the intestinal 2. Indirect or unpredictable or idiosyncratic, when the
tract. The main drug metabolising system resides in the drug or one of its metabolites acts as a hapten and induces
microsomal fraction of the smooth endoplasmic reticulum hypersensitivity in the host. In many instances, drug
of the liver cells via P-450 cytochrome and cytochrome hepatotoxicity is associated with appearance of
reductase enzyme systems. Other steps involved in the drug autoantibodies to liver-kidney microsomes (i.e. anti-LKM2)
metabolism are its conjugation with an endogenous mole- directed against cytochrome P450 enzyme. The hepato-
cule, its active transport from the hepatocytes and ultimately toxicity by this group does not occur regularly in all
its excretion in the bile or in urine depending upon the individuals and the effects are usually not dose-related e.g.
molecular weight of the substance. A number of risk factors acetaminophen.
618 TABLE 21.7: Classification of Hepatic Drug Reactions. of several diffuse diseases causing hepatocellular injury and
is characterised by the following 4 features:
Pathologic Changes Agents
1. It involves the entire liver.
A. ACUTE LIVER DISEASE 2. The normal lobular architecture of hepatic parenchyma
1. Zonal necrosis Carbon tetrachloride is disorganised.
Acetaminophen 3. There is formation of nodules separated from one another
Halothane by irregular bands of fibrosis.
2. Massive necrosis Halothane 4. It occurs following hepatocellular necrosis of varying
Acetaminophen etiology so that there are alternate areas of necrosis and
Methyldopa
regenerative nodules. However, regenerative nodules are not
3. Fatty change Tetracycline essential for diagnosis of cirrhosis since biliary cirrhosis and
Salicylates cirrhosis in haemochromatosis have little regeneration.
Methotrexate
Ethanol
PATHOGENESIS
4. Hepatitis Methyldopa Irrespective of the etiology, cirrhosis in general is initiated
Isoniazid
Halothane by hepatocellular necrosis. Continued destruction of
Ketoconazole hepatocytes causes collapse of normal lobular hepatic
parenchyma followed by fibrosis around necrotic liver cells
5. Granuloma formation Sulfonamides
Methyldopa and proliferated ductules and there is formation of
Quinidine compensatory regenerative nodules.
Allopurinol
FIBROGENESIS. Fibrosis in the liver lobules may be portal-
6. Cholestasis Sex hormones (including central, portal-portal, or both. The mechanism of fibrosis is
oral contraceptives) by increased synthesis of all types of collagen and increase
Chlorpromazine in the number of collagen-producing cells. In cirrhosis, there
Nitrofurantoin
is proliferation of fat-storing Ito cells underlying the
7. Veno-occlusive disease Cytotoxic drugs sinusoidal epithelium which become transformed into
8. Hepatic/portal vein Oral contraceptives myofibroblasts and fibrocytes. Besides collagen, two
SECTION III
thrombosis glycoproteins, fibronectin and laminin, are deposited in
excessive amounts in area of liver cell damage. The nature
B. CHRONIC LIVER DISEASE
of factors acting as stimulants for fibrosis is not clearly
1. Fibrosis-cirrhosis Methotrexate known, but possible candidate mediators are lymphokines
2. Focal nodular Vinyl chloride and monokines.
hyperplasia Vitamin A REGENERATIVE NODULE. The cause of compensatory
Sex hormones
proliferation of hepatocytes to form regenerative nodules is
3. Adenoma Sex hormones obscure. Possibly, growth factors, chalones and hormonal
4. Hepatocellular carcinoma Sex hormones imbalance, play a role in regeneration.
CLASSIFICATION
Systemic Pathology
A simplified clinicopathologic classification of important
hepatic drug reactions and the agents causing them is Cirrhosis can be classified on the basis of morphology and
presented in Table 21.7. The changes produced by etiology (Table 21.8).
hepatotoxic agents may vary from mild, which are diagnosed A. MORPHOLOGIC CLASSIFICATION. There are 3
only by elevated serum transaminases, to instances of morphologic types of cirrhosis—micronodular, macro-
massive necrosis and death. The pathologic changes by nodular and mixed. Each of these forms may have an active
hepatotoxins include 2 large categories: and inactive form.
1. Acute liver disease characterised by cholestasis, An active form is characterised by continuing hepato-
hepatocellular necrosis, fatty change, granulomatous reaction cellular necrosis and inflammatory reaction, a process that
or vascular disease. closely resembles chronic hepatitis.
2. Chronic liver disease characterised by variable degree of An inactive form, on the other hand, has no evidence of
fibrosis, cirrhosis or neoplasia. continuing hepatocellular necrosis and has sharply-defined
As such, the pathologic changes induced by hepatotoxins nodules of surviving hepatic parenchyma without any
are indistinguishable from the respective disease states. significant inflammation.
1. Micronodular cirrhosis. In micronodular cirrhosis, the
CIRRHOSIS
nodules are usually regular and small, less than 3 mm in
Cirrhosis of the liver is one of the ten leading causes of death diameter. There is diffuse involvement of all the hepatic
in the Western world. It represents the irreversible end-stage lobules forming nodules by thick fibrous septa which may
B. ETIOLOGIC CLASSIFICATION. Based on the etiologic 619
TABLE 21.8: Classification of Cirrhosis.
agent for cirrhosis, various categories of cirrhosis are
A. Morphologic B. Etiologic
described as given in Table 21.8.
I. Micronodular 1. Alcoholic cirrhosis
(nodules less than 3 mm) (the most common, 60-70%) SPECIFIC TYPES OF CIRRHOSIS
II. Macronodular 2. Post-necrotic cirrhosis (10%)
(nodules more than 3 mm) 3. Biliary cirrhosis (5-10%) Alcoholic Liver Disease and Cirrhosis
III. Mixed 4. Pigment cirrhosis in
haemochromatosis (5%) Alcoholic liver disease is the term used to describe the
5. Cirrhosis in Wilson’s disease spectrum of liver injury associated with acute and chronic
6. Cirrhosis in α-1-antitrypsin alcoholism. There are three sequential stages in alcoholic liver
deficiency disease: alcoholic steatosis (fatty liver), alcoholic hepatitis and
7. Cardiac cirrhosis alcoholic cirrhosis.
8. Indian childhood cirrhosis (ICC) Before discussing the features of alcoholic liver disease
9. Cirrhosis in autoimmune hepatitis and cirrhosis, a brief outline of ethanol metabolism is
10. Cirrhosis in non-alcoholic outlined below and is discussed earlier in Chapter 9 (page
steatohepatitis 239).
11. Miscellaneous forms of
cirrhosis (metabolic, infectious, ETHANOL METABOLISM. One gram of alcohol gives 7
GI, infiltrative) diseases calories. But alcohol cannot be stored in the body and must
12. Cryptogenic cirrhosis
undergo obligatory oxidation, chiefly in the liver. Thus, these
empty calories make no contribution to nutrition other than
be portal-portal, portal-central, or both. The micronodular to give energy.
cirrhosis includes etiologic type of alcoholic cirrhosis (or Ethanol after ingestion and absorption from the small
nutritional cirrhosis or Laennec’s cirrhosis) and represents bowel circulates through the liver where about 90% of it is
impaired capacity for regrowth as seen in alcoholism, oxidised to acetate by a two-step enzymatic process involving
malnutrition, severe anaemia and old age. two enzymes: alcohol dehydrogenase (ADH) present in the CHAPTER 21
2. Macronodular cirrhosis. In this type, the nodules are of cytosol, and acetaldehyde dehydrogenase (ALDH) in the
variable size and are generally larger than 3 mm in diameter. mitochondria of hepatocytes (Fig. 21.21). The remaining 10%
The pattern of involvement is more irregular than in of ethanol is oxidised elsewhere in the body.
micronodular cirrhosis, sparing some portal tracts and First step: Ethanol is catabolised to acetaldehyde in the liver
central veins, and more marked evidence of regeneration. by the following three pathways, one major and two minor:
Macronodular cirrhosis corresponds to post-necrotic (or post- i) In the cytosol, by the major rate-limiting pathway of
hepatitis) cirrhosis of the etiologic classification.
alcohol dehydrogenase (ADH).
3. Mixed cirrhosis. In mixed type, some parts of the liver ii) In the smooth endoplasmic reticulum, via microsomal P-450
show micronodular appearance while other parts show oxidases (also called microsomal ethanol oxidising system,
macronodular pattern. All the portal tracts and central veins MEOS), where only part of ethanol is metabolised.
are not involved by fibrosis but instead some of them are
spared. Mixed pattern is a kind of incomplete expression of iii) In the peroxisomes, minor pathway via catalase such as
2
2
micronodular cirrhosis. H O . The Liver, Biliary Tract and Exocrine Pancreas
Figure 21.21 Metabolism of ethanol in the liver. Thickness and intensity of colour of arrows on left side of figure corresponds to extent of
metabolic pathway followed (ADH = alcohol dehydrogenase; ALDH or ACDH = hepatic acetaldehyde dehydrogenase; NAD = nicotinamide adenine
dinucleotide; NADH = reduced NAD).
620 Acetaldehyde is toxic and may cause membrane damage disease. Lesions similar to alcoholic cirrhosis may develop
and cell necrosis. Simultaneously, the cofactor nicotinamide- in non-alcoholic patients who have had viral infections in
adenine dinucleotide (NAD) which is a hydrogen acceptor, the past.
is reduced to NADH. 5. Genetic factors. The rate of ethanol metabolism is under
Second step: The second step occurs in the mitochondria genetic control. It is chiefly related to altered rates of
where acetaldehyde is converted to acetate with ALDH elimination of ethanol due to genetic polymorphism for the
acting as a co-enzyme. Most of the acetate on leaving the two main enzyme systems, MEOS (microsomal P-450
liver is finally oxidised to carbon dioxide and water, or oxidases) and alcohol dehydrogenase (ADH). Various HLA
converted by the citric acid cycle to other compounds histocompatibility types have been associated with
including fatty acids. Simultaneously, the same cofactor, susceptibility of different populations to alcoholic liver
NAD, is reduced to NADH resulting in increased NADH: damage but no single genotype has been identified yet.
NAD redox ratio which is the basic biochemical alteration 6. Hepatitis C infection. Concurrent infection with HCV is
occurring during ethanol metabolism. A close estimate of an important risk factor for progression of alcoholic liver
NADH:NAD ratio is measured by the ratio of its oxidised disease. HCV infection in chronic alcoholic leads to
and reduced metabolites in the form of lactate-pyruvate ratio development of alcoholic liver disease with much less alcohol
and β-hydroxy butyrate-acetoacetate ratio. consumption (20-50 g/day), disease progression at a younger
RISK FACTORS FOR ALCOHOLIC LIVER DISEASE. All age, having greater severity, and increased risk to develop
those who indulge in alcohol abuse do not develop liver cirrhosis and hepatocellular carcinoma, and overall poorer
damage. The incidence of cirrhosis among alcoholics at survival.
autopsy is about 10-15%. Why some individuals are PATHOGENESIS. Exact pathogenesis of alcoholic liver
predisposed to alcoholic cirrhosis is not clearly known, but injury is yet unclear as to why only some chronic alcoholics
a few risk factors have been implicated. These are as under: develop the complete sequence of changes in the liver while
1. Drinking patterns. Most epidemiologic studies have others don’t. However, knowledge and understanding of
attributed alcoholic cirrhosis to chronic alcoholism. Available the ethanol metabolism has resulted in discarding the old
evidence suggests that chronic and excessive consumption concept of liver injury due to malnutrition. Instead, now it
of alcohol invariably leads to fatty liver in >90% of chronic is known that ethanol and its metabolites are responsible for
alcoholics, progression to alcoholic hepatitis in 10-20% cases, ill-effects on the liver in a susceptible chronic alcoholic having
and eventually to alcoholic cirrhosis in more than 10 years. above-mentioned risk factors. Briefly, the biomedical and
SECTION III
It is generally agreed that continued daily imbibing of 60-80 cellular pathogenesis due to chronic alcohol consumption
gm of ethanol in any type of alcoholic beverage for at least culminating in morphologic lesions of alcoholic steatosis
10 years is likely to result in alcoholic cirrhosis. Liver injury (fatty liver), alcoholic hepatitis and alcoholic cirrhosis can
is related to the quantity of ethanol contained in alcoholic be explained as under and is schematically illustrated in
beverage consumed and its duration, but not related to the Fig. 21.22:
type of alcoholic beverage consumed. Ethanol content in an 1. Direct hepatotoxicity by ethanol. There is evidence to
alcoholic beverage is given on the label of the container, but suggest that ethanol ingestion for a period of 8-10 days regu-
in general, it s about 4-6% in beer, 10-12% in wine, and about larly may cause direct hepatotoxic effect on the liver and
40-50% in brandy, whisky and scotch. Intermittent drinking produce fatty change. Ethanol is directly toxic to micro-
for long duration is less harmful since the liver is given tubules, mitochondria and membrane of hepatocytes.
chance to recover.
Systemic Pathology
2. Gender. Women have increased susceptibility to develop 2. Hepatotoxicity by ethanol metabolites. The major
hepatotoxic effects of ethanol are exerted by its metabolites,
advanced alcoholic liver disease with much lesser alcohol chiefly acetaldehyde. Acetaldehyde levels in blood are
intake (20-40 g/day). This gender difference in disease elevated in chronic alcoholics. Acetaldehyde produces
progression is unclear but is probably linked to effects of hepatotoxicity by production of two adducts:
oestrogen. i) Production of protein-aldehyde adducts which are extremely
3. Malnutrition. Absolute or relative malnutrition of toxic and can cause cytoskeletal and membrane damage and
proteins and vitamins is regarded as a contributory factor in bring about hepatocellular necrosis.
the evolution of cirrhosis. The combination of chronic alcohol ii) Formation of malon-di-aldehyde-acetaldehyde (MAA) adducts
ingestion and impaired nutrition leads to alcoholic liver which produce autoantibodies and initiate autoimmune
disease and not malnutrition per se. It appears that calories response. Theses adducts have also a role in hepatic
derived from alcohol displace other nutrients leading to fibrogenesis due to peroxisome proliferator-activated
malnutrition and deficiency of vitamins in alcoholics. receptor (PPAR)-γ on hepatocytes.
Additional factors contributing to malnutrition in alcoholics
are chronic gastritis and pancreatitis. The evidence in favour 3. Oxidative stress. Oxidation of ethanol by the cytochrome-
of synergistic effect of malnutrition in chronic alcoholism 450 oxidases (MEOS) leads to generation of free radicals
comes from clinical and morphologic improvement in cases which causes oxidative damage to the membranes and
of alcoholic cirrhosis on treatment with protein-rich diets. proteins.
4. Infections. Intercurrent bacterial infections are common 4. Immunological mechanism. Cell-mediated immunity is
in cirrhotic patients and may accelerate the course of the impaired in alcoholic liver disease. Ethanol causes direct
occurrence of gout, impaired gluconeogenesis and altered 621
steroid metabolism.
8. Retention of liver cell water and proteins. Alcohol is
inhibitory to secretion of newly-synthesised proteins by the
liver leading to their retention in the hepatocytes. Water is
simultaneously retained in the cell in proportion to the
protein and results in swelling of hepatocytes resulting in
hepatomegaly in alcoholics.
9. Hypoxia. Chronic ingestion of alcohol results in increased
oxygen demand by the liver resulting in a hypoxic state
which causes hepatocellular necrosis in centrilobular zone
(zone 3). Redox changes are also more marked in zone 3.
10. Increased liver fat. The origin of fat in the body was
discussed in Chapter 3 (page 37). In chronic alcoholism, there
is rise in the amount of fat available to the liver which could
be from exogenous (dietary) sources, excess mobilisation
from adipose tissue or increased lipid synthesis by the liver
itself. This may account for lipid accumulation in the
hepatocytes.
MORPHOLOGIC FEATURES. Three types of morpho-
logic lesions are described in alcoholic liver disease—
alcoholic steatosis (fatty liver), alcoholic hepatitis and
alcoholic cirrhosis.
1. ALCOHOLIC STEATOSIS (FATTY LIVER). The CHAPTER 21
Figure 21.22 Pathogenesis of alcoholic liver disease. morphologic changes in fatty change in liver have already
been described on page 37 and are briefly considered here.
immunologic attack on hepatocytes. In a proportion of cases, Grossly, the liver is enlarged, yellow, greasy and firm with
alcohol-related liver cell injury continues unabated despite a smooth and glistening capsule.
cessation of alcohol consumption which is attributed to Microscopically, the features consist of initial micro-
immunologic mechanisms. Immunological mechanism may vesicular droplets of fat in the hepatocyte cytoplasm
also explain the genesis of Mallory’s alcoholic hyalin though followed by more common and pronounced feature of
more favoured hypothesis for its origin is the aggregation of macrovesicular large droplets of fat displacing the nucleus
intermediate filaments of prekeratin type due to alcohol- to the periphery (Fig. 21.23). Fat cysts may develop due to
induced disorganisation of cytoskeleton. coalescence and rupture of fat-containing hepatocytes.
Less often, lipogranulomas consisting of collection of
5. Inflammation. Chronic ethanol ingestion is not only
injurious to hepatocytes but also damages the intestinal cells. lymphocytes, macrophages and some multinucleate giant
The injured intestinal cells elaborate endotoxins which cells may be found.
release proinflammatory cytokines, chiefly tumour necrosis 2. ALCOHOLIC HEPATITIS. Alcoholic hepatitis
factor-α, IL-1, IL-6 and TGF-β. These cytokines and develops acutely, usually following a bout of heavy drin- The Liver, Biliary Tract and Exocrine Pancreas
endotoxinaemia produce apoptosis and necrosis of king. Repeated episodes of alcoholic hepatitis super-
hepatocytes and initiate inflammatory reaction in the alcohol imposed on pre-existing fatty liver are almost certainly a
damaged liver. forerunner of alcoholic cirrhosis.
Histologically, the features of alcoholic hepatitis are as
6. Fibrogenesis. Main event facilitating hepatic fibrogenesis
is activation of stellate cells by various stimuli: follows (Fig. 21.24):
i) by damaged hepatocytes, i) Hepatocellular necrosis: Single or small clusters of
ii) by malon-di-aldehyde-acetaldehyde adducts, hepatocytes, especially in the centrilobular area (zone 3),
iii) by activated Kupffer cells, and undergo ballooning degeneration and necrosis.
iv) direct stimulation by acetaldehyde. ii) Mallory bodies or alcoholic hyalin: These are
All forms of collagen are increased and there is increased eosinophilic, intracytoplasmic inclusions seen in
transformation of fat-storing lto cells into myofibroblasts and perinuclear location within swollen and ballooned
fibrocytes. hepatocytes. They represent aggregates of cytoskeletal
intermediate filaments (prekeratin). They can be best
7. Increased redox ratio. Marked increase in the NADH:NAD visualised with connective tissue stains like Masson’s
redox ratio in the hepatocytes results in increased redox ratio trichrome and chromophobe aniline blue, or by the use
of lactate-pyruvate, leading to lactic acidosis. This altered of immunoperoxidase methods. Mallory bodies are highly
redox potential has been implicated in a number of metabolic suggestive of, but not specific for, alcoholic hepatitis since
consequences such as in fatty liver, collagen formation,
622
Figure 21.23 Fatty liver (alcoholic steatosis). Most of the hepatocytes are distended with large lipid vacuoles with peripherally displaced nuclei.
Mallory bodies are also found in certain other conditions 3. ALCOHOLIC CIRRHOSIS. Alcoholic cirrhosis is the
such as: primary biliary cirrhosis, Indian childhood most common form of lesion, constituting 60-70% of all
cirrhosis, cholestatic syndromes, Wilson’s disease, cases of cirrhosis. Several terms have been used for this
intestinal bypass surgery, focal nodular hyperplasia and type of cirrhosis such as Laennec’s cirrhosis, portal cirrhosis,
hepatocellular carcinoma. hobnail cirrhosis, nutritional cirrhosis, diffuse cirrhosis and
iii) Inflammatory response: The areas of hepatocellular micronodular cirrhosis.
necrosis and regions of Mallory bodies are associated with Grossly, alcoholic cirrhosis classically begins as
an inflammatory infiltrate, chiefly consisting of micronodular cirrhosis (nodules less than 3 mm diameter),
SECTION III
polymorphs and some scattered mononuclear cells. In the liver being large, fatty and weighing usually above
more extensive necrosis, the inflammatory infiltrate is 2 kg (Fig. 21.25). Eventually over a span of years, the liver
more widespread and may involve the entire lobule. shrinks to less than 1 kg in weight, becomes non-fatty,
iv) Fibrosis: Most cases of alcoholic hepatitis are having macronodular cirrhosis (nodules larger than 3 mm
accompanied by pericellular and perivenular fibrosis, in diameter), resembling post-necrotic cirrhosis. The
producing a web-like or chickenwire-like appearance. This nodules of the liver due to their fat content are tawny-
is also termed as creeping collagenosis. yellow, on the basis of which Laennec in 1818 introduced
Systemic Pathology
Figure 21.24 Alcoholic hepatitis. Liver cells show ballooning degeneration and necrosis with some containing Mallory’s hyalin (Inbox). Fatty
change and clusters of neutrophils are also present.
623
Figure 21.25 Alcoholic cirrhosis, showing the typical micronodular
pattern in gross specimen. There is diffuse nodularity (nodules less than
3 mm diameter) on sectioned surface of the liver.
the term cirrhosis first of all (from Greek kirrhos = tawny). i) Nodular pattern: Normal lobular architecture is CHAPTER 21
The surface of liver in alcoholic cirrhosis is studded with effaced in which central veins are hard to find and is
diffuse nodules which vary little in size, producing replaced with nodule formation.
hobnail liver (because of the resemblance of the surface ii) Fibrous septa: The fibrous septa that divide the hepatic
with the sole of an old-fashioned shoe having short nails parenchyma into nodules are initially delicate and extend
with heavy heads). On cut section, spheroidal or angular from central vein to portal regions, or portal tract to portal
nodules of fibrous septa are seen. tract, or both. As the fibrous scarring increases with time,
Microscopically, alcoholic cirrhosis is a progressive the fibrous septa become dense and more confluent.
alcoholic liver disease. Its features include the following iii) Hepatic parenchyma: The hepatocytes in the islands
(Fig. 21.26): of surviving parenchyma undergo slow proliferation The Liver, Biliary Tract and Exocrine Pancreas
Figure 21.26 Alcoholic cirrhosis, microscopic appearance. It shows nearly uniform-sized micronodules, devoid of central veins and having
thick fibrous septa dividing them. There is minimal inflammation and some reactive bile duct proliferation in the septa.
624 Post-necrotic Cirrhosis
forming regenerative nodules having disorganised masses
of hepatocytes. The hepatic parenchyma within the Post-necrotic cirrhosis, also termed post-hepatitic cirrhosis,
nodules shows extensive fatty change early in the disease. macronodular cirrhosis and coarsely nodular cirrhosis, is
But as the fibrous septa become more thick, the amount characterised by large and irregular nodules with broad
of fat in hepatocytes is reduced. Thus, there is an inverse bands of connective tissue and occurring most commonly
relationship between the amount of fat and the amount after previous viral hepatitis.
of fibrous scarring in the nodules. ETIOLOGY. Based on epidemiologic and serologic studies,
iv) Necrosis, inflammation and bile duct proliferation: the following factors have been implicated in the etiology of
The etiologic clue to diagnosis in the form of Mallory post-necrotic cirrhosis.
bodies is hard to find in a fully-developed alcoholic 1. Viral hepatitis. About 25% of patients give history of
cirrhosis. The fibrous septa usually contain sparse recent or remote attacks of acute viral hepatitis followed by
infiltrate of mononuclear cells with some bile duct chronic viral hepatitis. Most common association is with
proliferation. Bile stasis and increased cytoplasmic hepatitis B and C; hepatitis A is not known to evolve into
haemosiderin deposits due to enhanced iron absorption
in alcoholic cirrhosis are some other noticeable findings. cirrhosis. It is estimated that about 20% cases of HBV chronic
hepatitis and about 20-30% cases of HCV chronic hepatitis
LABORATORY DIAGNOSIS. The clinical manifestations go to develop cirrhosis over 20-30 years.
and complications of cirrhosis in general are described on 2. Drugs and chemical hepatotoxins. A small percentage
page 630. The laboratory findings in the course of alcoholic of cases may have origin from toxicity due to chemicals and
liver disease may be quite variable and liver biopsy is drugs such as phosphorus, carbon tetrachloride, mushroom
necessary in doubtful cases. Progressive form of the disease, poisoning, acetaminophen and α-methyl dopa.
however, generally presents the following biochemical and 3. Others. Certain infections (e.g. brucellosis), parasitic
haematological alterations: infestations (e.g. clonorchiasis), metabolic diseases (e.g.
1. Elevated transaminases: increase in SGOT (AST) is more Wilson’s disease or hepatolenticular degeneration) and
than that of SGPT (ALT). advanced alcoholic liver disease may produce a picture of
2. Rise in serum γ-glutamyl transpeptidase (γ-GT). post-necrotic cirrhosis.
3. Elevation in serum alkaline phosphatase. 4. Idiopathic. After all these causes have been excluded, a
4. Hyperbilirubinaemia. group of cases remain in which the etiology is unknown.
5. Hypoproteinaemia with reversal of albumin-globulin
SECTION III
ratio. MORPHOLOGIC FEATURES. Typically, post-necrotic
6. Prolonged prothrombin time and partial thromboplastin cirrhosis is macronodular type.
time. Grossly, the liver is usually small, weighing less than
7. Anaemia. 1 kg, having distorted shape with irregular and coarse
8. Neutrophilic leucocytosis in alcoholic hepatitis and in scars and nodules of varying size (Fig. 21.27). Sectioned
secondary infections.
Systemic Pathology
Figure 21.27 Post-necrotic cirrhosis, showing the typical irregular
macronodular pattern (nodules larger than 3 mm diameter). Externally
the liver is small, distorted and irregularly scarred.
625
Figure 21.28 Post-necrotic cirrhosis. Fibrous septa dividing the hepatic parenchyma into nodules are thick and contain prominent mononuclear
inflammatory cell infiltrate and bile ductular hyperplasia. A few intact hepatic lobules remain.
surface shows scars and nodules varying in diameter from Biliary Cirrhosis
3 mm to a few centimeters. Biliary cirrhosis is defined as a chronic disorder characterised
Microscopically, the features are as follows (Fig. 21.28): by clinical, biochemical and morphological features of long- CHAPTER 21
1. Nodular pattern: The normal lobular architecture of continued cholestasis of intrahepatic or extrahepatic origin.
hepatic parenchyma is mostly lost and is replaced by Biliary cirrhosis is of following types:
nodules larger than those in alcoholic cirrhosis. However, Primary biliary cirrhosis in which the destructive process
uninvolved portal tracts and central veins in the hepatic of unknown etiology affects intrahepatic bile ducts.
lobules can still be seen in some parts of surviving Secondary biliary cirrhosis resulting from prolonged
parenchyma. mechanical obstruction of the extrahepatic biliary passages.
2. Fibrous septa: The fibrous septa dividing the variable- Primary sclerosing cholangitis and autoimmune
sized nodules are generally thick. cholangiopathy causing biliary cirrhosis.
3. Necrosis, inflammation and bile duct proliferation: ETIOLOGY. The etiology of these forms of biliary cirrhosis
Active liver cell necrosis is usually inconspicuous. Fibrous is distinctive:
septa contain prominent mononuclear inflammatory cell A. Primary biliary cirrhosis. The etiology of this type
infiltrate which may even form follicles, especially in cases remains unknown. However, a few factors have been
following HCV chronic hepatitis. Often there is extensive implicated:
proliferation of bile ductules derived from collapsed liver 1. The condition is predominant in middle-aged women
lobules. (male: female ratio = 1:9) and has led to the suggestion of a The Liver, Biliary Tract and Exocrine Pancreas
4. Hepatic parenchyma: Liver cells vary considerably in possible endocrine origin.
size and multiple large nuclei are common in regenerative 2. Familial incidence has been observed suggesting the role
nodules. Fatty change may or may not be present in the of some genetic influence and certain HLA types.
hepatocytes. 3. There is elevated cholesterol level with appearance of
xanthoma and xanthelasma. Hepatomegaly and chronic liver
disease are late features of the disease.
CLINICAL FEATURES. Besides the general clinical features
described on page 630, post-necrotic cirrhosis is seen as 4. However, presently the most widely accepted hypothesis
is autoimmune origin of the disease. In support are the
frequent in women as in men, especially in the younger age following observations:
group. Like in alcoholic cirrhosis, the patients may remain increased incidence of associated autoimmune diseases
asymptomatic or may present with prominent signs and (e.g. scleroderma, Sjögren’s syndrome, CREST syndrome,
symptoms of chronic hepatitis (page 611). Splenomegaly and and autoimmune thyroiditis),
hypersplenism are other prominent features. The results of circulating anti-mitochondrial antibody of IgG class
haematologic and liver function test are similar to those of detected in more than 90% cases;
alcoholic cirrhosis. Out of the various types of cirrhosis, post- elevated levels of immunoglobulins, particularly of IgM;
necrotic cirrhosis, especially when related to hepatitis B and increased levels of circulating immune complexes;
C virus infection in early life, is more frequently associated decreased number of circulating T-cells; and
with hepatocellular carcinoma. accumulation of T cells around bile ducts.
626 B. Secondary biliary cirrhosis. Most cases of secondary
biliary cirrhosis result from prolonged obstruction of
extrahepatic biliary passages (page 599). These causes
include the following:
1. Extrahepatic cholelithiasis, most common
2. Biliary atresia
3. Cancer of biliary tree and of head of pancreas
4. Postoperative strictures with superimposed ascending
cholangitis.
C. Cirrhosis due to primary sclerosing cholangitis. Primary
or idiopathic sclerosing cholangitis is a chronic cholestatic
syndrome of unknown etiology. It is characterised by
progressive, inflammatory, sclerosing and obliterative
process affecting the entire biliary passages, both extra-
hepatic and intrahepatic ducts. Although etiology remains
unknown, various mechanisms have been postulated which
include viral and bacterial infections, immunologic injury, Figure 21.29 Primary biliary cirrhosis, diagrammatic representation.
toxins, and genetic predisposition. There are fibrous scars dividing the hepatic parenchyma into the
micronodules. The fibrous septa contain prominent lymphoid infiltrate
MORPHOLOGIC FEATURES. Grossly, in biliary and proliferated bile ducts. Many of the hepatocytes contain elongated
cirrhosis of all types, the liver is initially enlarged and bile plugs.
characteristically greenish in appearance, but later becomes
smaller, firmer and coarsely micronodular. In cirrohosis 4. Progressive expansion of the portal tract by fibrosis and
due to primary sclerosing cholangitis, there is charac- evolution into micronodular cirrhosis.
teristic beading of intra- and extrahepatic bile ducts due C. Cirrhosis due to primary sclerosing cholangitis:
to irregular strictures and dilatation. Following changes are seen:
Microscopically, the features of intra- and extrahepatic 1. Fibrosing cholangitis with lymphocytic infiltrate around
cholestasis correspond to primary and secondary biliary bile ducts with segmental involvement.
cirrhosis respectively discussed on page 599. The salient 2. Periductal fibrosis with eventual obliteration of lumen
SECTION III
features of various forms of biliary cirrhosis are as under: of affected bile ducts.
A. Primary biliary cirrhosis: The diagnostic histologic 3. Intervening bile ducts are dilated, tortuous and
feature is a chronic, non-suppurative, destructive inflamed.
cholangitis involving intrahepatic bile ducts. The disease 4. Late cases show cholestasis and full-blown picture of
evolves through the following 4 histologic states: biliary cirrhosis.
Stage I: There are florid bile duct lesions confined to portal
tracts. The changes in the affected area consist of CLINICAL FEATURES. Clinical features of the three types
destruction of bile ducts, presence of bile plugs, infiltration of biliary cirrhosis are variable:
with acute and chronic inflammatory cells and sometimes
formation of granulomas and lymphoid follicles. Primary biliary cirrhosis may remain asymptomatic for
Systemic Pathology
Stage II: There is ductular proliferation. The ductal involve- months to years. Symptoms develop insidiously. Basically,
ment is quite widespread with very few normal bile ducts. it is a cholestatic disorder. The patients present with
The inflammatory infiltrate too extends beyond the portal persistent pruritus, dark urine, pale stools, steatorrhoea,
tracts into surrounding hepatic parenchyma. Periportal jaundice and skin pigmentation. The earliest laboratory
Mallory bodies may be present. finding is a markedly elevated serum alkaline phosphatase
level. Elevation of serum lipids is accompanied by
Stage III: This stage is characterised by fibrous scarring appearance of periorbital xanthelasma and xanthomas over
interconnecting the portal areas. There is diminished
inflammatory infiltrate and reduced number of bile ducts. joints. Death usually results from hepatic failure, variceal
Stage IV: Well-formed micronodular pattern of cirrhosis bleeding, intercurrent infections and concomitant
develops in a period of a few years (Fig. 21.29). development of cancers of liver and breast.
B. Secondary biliary cirrhosis: Prolonged obstruction of The diagnosis of secondary biliary cirrhosis is considered
extrahepatic bile ducts may produce the following in patients with previous history of gallstones, biliary tract
histologic changes: surgery or clinical features of ascending cholangitis.
1. Bile stasis, degeneration and focal areas of centrilobular The patients of primary sclerosing cholangitis may
necrosis of hepatocytes. remain asymptomatic or may show features of cholestatic
2. Proliferation, dilatation and rupture of bile ductules jaundice (raised alkaline phosphatase, pruritus, fatigue). Late
in the portal area with formation of bile lakes. cases show manifestations of chronic liver disease. The
3. Cholangitis, sterile or pyogenic, with accumulation of disease occurs in 3rd to 5th decade of life with two fold
polymorphs around the bile ducts. preponderance in males.
TABLE 21.9: Contrasting Features of Major Forms of Biliary Cirrhosis. 627
Feature Primary Biliary Cirrhosis Secondary Biliary Cirrhosis Primary Sclerosing Cholangitis
1. Etiology Possibly autoimmune; association Extrahepatic biliary Possibly autoimmune; association
with other autoimmune diseases obstruction; biliary atresia with inflammatory bowel disease
2. Age and sex Middle-aged women Any age and either sex Middle age
Male: Female = 1:9 Male: Female = 2:1
3. Laboratory tests ↑ ↑ ↑ ↑ ↑ Alkaline phosphatase ↑ ↑ ↑ ↑ ↑ Alkaline phosphatase ↑ ↑ ↑ ↑ ↑ Alkaline phosphatase
↑ ↑ ↑ ↑ ↑ Conjugated bilirubin ↑ ↑ ↑ ↑ ↑ Conjugated bilirubin ↑ ↑ ↑ ↑ ↑ Conjugated bilirubin
Autoantibodies present Hypergammaglobulinaemia
4. Pathologic changes Chronic destructive; Bile stasis in bile Fibrosing cholangitis
cholangitis of intrahepatic ducts, and sterile or with periductal fibrosis
bile ducts pyogenic cholangitis
The contrasting features of three main types of absorption excretion level leading to excessive accumulation
intrahepatic disorders leading to biliary cirrhosis are of iron. The excess iron in primary haemochromatosis is
summarised in Table 21.9. deposited mainly in the cytoplasm of parenchymal cells of
organs such as the liver, pancreas, spleen, heart and
Pigment Cirrhosis in Haemochromatosis endocrine glands. Tissue injury results from iron-laden
Haemochromatosis is an iron-storage disorder in which there lysosomes of parenchymal cells and lipid peroxidation of cell
is excessive accumulation of iron in parenchymal cells with organelles by excess iron.
eventual tissue damage and functional insufficiency of In secondary or acquired haemochromatosis, there is
organs such as the liver, pancreas, heart and pituitary gland. excessive accumulation of iron due to acquired causes like
The condition is characterised by a triad of features— ineffective erythropoiesis, defective haemoglobin synthesis, CHAPTER 21
micronodular pigment cirrhosis, diabetes mellitus and skin multiple blood transfusions and enhanced absorption of iron
pigmentation. On the basis of the last two features, the disease due to alcohol consumption. The last-named phenomenon
has also come to be termed as ‘bronze diabetes’. Males is observed in Bantu siderosis affecting South African Bantu
predominate and manifest earlier since women have tribals who consume large quantities of home-brew prepared
physiologic iron loss delaying the effects of excessive in iron vessels. Cases of secondary haemochromatosis have
accumulation of iron. Haemochromatosis exists in 2 main increased iron storage within the reticuloendothelial system
forms: and liver. However, the magnitude of the iron excess in
1. Idiopathic (primary, genetic) haemochromatosis is an secondary haemochromatosis is generally insufficient to
autosomal recessive disorder of excessive accumulation of cause tissue damage.
iron. It is associated with overexpression of HFE gene located
on chromosome 6 close to the HLA gene locus, and normally MORPHOLOGIC FEATURES. Excessive deposition of
regulates intestinal absorption of iron. Mutated iron in organs and tissues is ferritin and haemosiderin,
(overexpressed) HFE gene complexes with transferrin both of which appear as golden-yellow pigment granules
receptor on intestinal crypt epithelial cells and results in in the cytoplasm of affected parenchymal cells and
excessive absoption of dietary iron throughout life. haemosiderin stains positively with Prussian blue
2. Secondary (acquired) haemochromatosis is gross iron reaction. The organs most frequently affected are the liver The Liver, Biliary Tract and Exocrine Pancreas
overload with tissue injury arising secondary to other and pancreas, and to a lesser extent, the heart, endocrine
diseases such as thalassaemia, sideroblastic anaemias, glands, skin, synovium and testis.
alcoholic cirrhosis or multiple transfusions. In the liver, excess of pigment accumulates in the
ETIOPATHOGENESIS. A general discussion of iron hepatocytes, and less often Kupffer cells and in bile duct
metabolism and iron excess states is given on page 41. epithelium. The deposits in the initial stage may be
Normally, the body iron content is 3-4 gm which is prominent in the periportal liver cells along with increased
maintained in such a way that intestinal mucosal absorp- fibrosis in the portal zone. Eventually, micronodular
tion of iron is equal to its loss. This amount is approximately cirrhosis develops. The deposits may produce grossly
1 mg/day in men and 1.5 mg/day in menstruating women. chocolate-brown colour of the liver and nodular surface.
In haemochromatosis, however, this amount goes up to 4 In the pancreas, pigmentation is less intense and is
mg/day or more, as evidenced by elevated serum iron found in the acinar and islet cells. The deposits in pancreas
(normal about 125 μg/dl) and increased serum transferrin produce diffuse interstitial fibrosis and atrophy of
saturation (normal 30%). parenchymal cells leading to occurrence of diabetes
In idiopathic or hereditary haemochromatosis, the mellitus.
primary mechanism of disease appears to be the genetic basis
in which the defect may either lie at the intestinal mucosal CLINICAL FEATURES. The major clinical manifestations
level causing excessive iron absorption, or at the post- of haemochromatosis include skin pigmentation, diabetes
628 mellitus, hepatic and cardiac dysfunction, arthropathy and MORPHOLOGIC FEATURES. The liver shows varying
hypogonadism. Characteristic bronze pigmentation is the grades of changes that include fatty change, acute and
presenting feature in about 90% of cases. Demonstration of chronic active hepatitis, submassive liver necrosis and
excessive parenchymal iron stores is possible by measure- macronodular cirrhosis. Mallory bodies are present in
ment of serum iron, determination of percent saturation of some cases. Copper is usually deposited in the periportal
transferrin, measurement of serum ferritin concentration, hepatocytes in the form of reddish granules in the
estimation of chelatable iron stores using chelating agent (e.g. cytoplasm or as reddish cytoplasmic coloration, stainable
desferrioxamine), and finally, by liver biopsy. Occurrence by rubeanic acid or rhodamine stains for copper.
of hepatocellular carcinoma is a late complication of Involvement of basal ganglia in the brain is seen in
haemochromatosis-induced cirrhosis. the form of toxic injury to neurons, in the cornea as
greenish-brown deposits of copper in Descemet’s
Cirrhosis in Wilson’s Disease
membrane, and in the kidney as fatty and hydropic
Wilson’s disease, also termed by a more descriptive desig- change.
nation of hepatolenticular degeneration, is an autosomal
recessive inherited disease of copper metabolism, Cirrhosis in αα αα α-1-Antitrypsin Deficiency
characterised by toxic accumulation of copper in many
tissues, chiefly the liver, brain and eye. These accumulations Alpha-1-antitrypsin deficiency is an autosomal codominant
lead to the triad of features: condition in which the homozygous state produces liver
1. Cirrhosis of the liver. disease (cirrhosis), pulmonary disease (emphysema), or both
2. Bilateral degeneration of the basal ganglia of the brain. (page 479). α-1-antitrypsin is a glycoprotein normally
synthesised in the rough endoplasmic reticulum of the
3. Greenish-brown pigmented rings in the periphery of the hepatocytes and is the most potent protease inhibitor (Pi). A
cornea (Kayser-Fleischer rings). single autosomal dominant gene coding for α-1-antitrypsin
The disease manifests predominantly in children and is located on long arm of chromosome 14 that codes for
young adults (5-30 years). Initially, the clinical manifestations immunoglobulin light chains too. Out of 24 different alleles
are referable to liver involvement such as jaundice and labelled alphabetically, PiMM is the most common normal
hepatomegaly (hepatic form) but later progressive phenotype, while the most frequent abnormal phenotype in
neuropsychiatric changes and Kayser-Fleischer rings in the α-1-antitrypsin deficiency leading to liver and/or lung
cornea appear.
disease is PiZZ in homozygote form. Other phenotypes in
SECTION III
PATHOGENESIS. The pathogenesis of Wilson’s disease is which liver disease occurs are PiSS and Pi-null in which
best understood when compared with normal copper serum α-1-antitrypsin value is nearly totally deficient.
metabolism. Intermediate phenotypes, PiMZ and PiSZ persons are
Normally, dietary copper is more than body’s predisposed to develop hepatocellular carcinoma.
requirement. Excess copper so absorbed through the stomach The patients may present with respiratory disease due
and duodenum is transported to the liver where it is to the development of emphysema, or may develop liver
incorporated into α -globulin to form ceruloplasmin, which dysfunction, or both. At birth or in neonates, the features of
2
is excreted by the liver via bile normally. Most of the plasma cholestatic jaundice of varying severity may appear. In
copper circulates as ceruloplasmin. Only minute amount of adolescence, the condition may evolve into hepatitis or
copper is excreted in the urine normally. cirrhosis which is usually well compensated.
In Wilson’s disease, the initial steps of dietary absorp-
Systemic Pathology
tion and transport of copper to the liver are normal but MORPHOLOGIC FEATURES. Pulmonary changes in α-
copper accumulates in the liver rather than being excreted 1-antitrypsin deficiency in the form of emphysema are
by the liver. The underlying defect in chromosome 13 is a described in Chapter 17. The hepatic changes vary
mutation in ATP7B gene, the normal hepatic copper- according to the age at which the deficiency becomes
excreting gene. Eventually, capacity of hepatocytes to store apparent. At birth or in neonates, the histologic features
copper is exceeded and copper is released into circulation consist of neonatal hepatitis that may be acute or ‘pure’
which then gets deposited in extrahepatic tissues such as the cholestasis. Micronodular or macronodular cirrhosis may
brain, eyes and others. However, increased copper in the appear in childhood or in adolescence in which the
kidney does not produce any serious renal dysfunction. diagnostic feature is the presence of intracellular,
Biochemical abnormalities in Wilson’s disease include the acidophilic, PAS-positive globules in the periportal
following: hepatocytes. Ultrastructurally, these globules consist of
1 Decreased serum ceruloplasmin (due to impaired synthesis dilated rough endoplasmic reticulum.
of apoceruloplasmin in damaged liver and defective
mobilisation of copper from hepatocellular lysosomes). Cardiac Cirrhosis
2. Increased hepatic copper in liver biopsy (due to excessive
accumulation of copper in the liver). Cardiac cirrhosis is an uncommon complication of severe
3. Increased urinary excretion of copper. right-sided congestive heart failure of long-standing duration
4. However, serum copper levels are of no diagnostic help (page 99). The common causes culminating in cardiac
and may vary from low-to-normal-to-high depend- ing upon cirrhosis are cor pulmonale, tricuspid insufficiency or
the stage of disease. constrictive pericarditis. The pressure in the right ventricle
is elevated which is transmitted to the liver via the inferior 2. Predominant elevation of aminotransferases (AST and 629
vena cava and hepatic veins. The patients generally have ALT).
enlarged and tender liver with mild liver dysfunction. 3. Hyperglobulinaemia (elevated IgG and γ-globulin).
Splenomegaly occurs due to simple passive congestion. 4. High serum titres of nuclear (ANA), smooth muscle (SMA),
and liver-kidney microsomal (LKM1) autoantibodies, and
MORPHOLOGIC FEATURES. Grossly, the liver is absence of antimitochondrial antibodies.
enlarged and firm with stretched Glisson’s capsule. 5. Concurrent presence of other autoimmune diseases.
Histologically, in acute stage, the hepatic sinusoids are 6. Presence of HLA DR3 or HLA DR4 markers.
dilated and congested with haemorrhagic necrosis of 7. Lack of prominent elevation of alkaline phosphatase.
centrilobular hepatocytes (central haemorrhagic necrosis). 8. Exclusion of chronic hepatitis of other known etiologies
Severe and more prolonged heart failure results in delicate (viral, toxic, genetic etc).
fibrous strands radiating from the central veins. These
fibrous strands may form interconnections leading to MORPHOLOGIC FEATURES. Autoimmune hepatitis is
cardiac cirrhosis and regenerative nodules. morphologically indistinguishable from chronic hepatitis
of viral etiology. Patients who survive active disease
Indian Childhood Cirrhosis develop crrhosis. There are features of burnt out chronic
autoimmune hepatitis accompanied with cirrhosis.
Indian childhood cirrhosis (ICC) is an unusual form of
cirrhosis seen in children between the age of 6 months and 3 Cirrhosis in Non-alcoholic Steatohepatitis
years in rural, middle class, Hindus in India and in parts of
South-East Asia and in the Middle-East. There is no role of Non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty
viral infection in its etiology. Instead, a combination of some liver disease (NAFLD) is a from of hepatitis resembling
common toxic effects and inherited abnormality of copper alcoholic liver disease but seen in nondrinkers of alcohol.
metabolism has been suggested. Death occurs due to hepatic The condition is seen more commonly in affluent western
failure within a year of diagnosis. socieities, has a strong association with obesity,
dyslipidaemia and type 2 diabetes mellitus. It is seen in
MORPHOLOGIC FEATURES. Five histologic types of youger patients with equal gender prevalence. Pateints are CHAPTER 21
ICC have been distinguished of which type II is the most generally asymptomatic and are diagnosed by routine
common. This form is characterised by the following biochemical tests.
features: MORPHOLOGIC FEATURES. The condition is a form of
i) Liver cell injury ranging from ballooning degeneration chronic hepatitis after known causes have been excluded.
to significant damage to hepatocytes. About 10-30% cases of NASH progress to increased fibrosis
ii) Prominent Mallory bodies in some hepatocytes without and develop cirrhosis.
fatty change.
iii) Neutrophilic and sometimes alongwith lymphocytic Miscellaneous Forms of Cirrhosis
infiltrate. In addition to the various types of cirrhosis just described, a
iv) Creeping pericellular fibrosis which may eventually few other uncommon types associated with different diseases
lead to fine micro-macro-nodular cirrhosis. are sometimes distinguished. These include the following:
v) There is significant deposition of copper and copper- 1. Metabolic disorders e.g. in galactosaemia, hereditary
associated proteins in hepatocytes, often more than what fructose intolerance, glycogen storage diseases.
is seen in Wilson’s disease. 2. Infectious diseases e.g. in brucellosis, schistosomiasis, The Liver, Biliary Tract and Exocrine Pancreas
Thus, the picture resembles acute alcoholic hepatitis syphilis (hepar lobatum) and toxoplasma infection.
but without the fatty change and with greatly impaired 3. Gastrointestinal disorders e.g. in inflammatory bowel
regeneration. There is marked increase in hepatic copper disease, cystic fibrosis of the pancreas and intestinal bypass
since the milk consumed by such infants is often boiled surgery for obesity.
and stored in copper vessels in India. The condition has 4. Infiltrative diseases e.g. in sarcoidosis.
to be distinguished from Wilson’s disease.
Cryptogenic Cirrhosis
Cirrhosis in Autoimmune Hepatitis
Finally, when all the known etiologic types of cirrhosis have
Autoimmune hepatitis (also called lupoid hepatitis) is a form been excluded, there remain patients with cirrhosis in whom
of chronic hepatitis characterised by continued hepatocellular the cause is unknown. These cases are grouped under a
injury, inflammation and fibrosis which may progress to
cirrhosis. The condition may run a variable natural history waste-basket diagnosis of cryptogenic cirrhosis (crypto =
concealed).
rangingfrom indolent to severe rapid course. This form of
hepatitis has prominent autoimmune etiology is supported NON-CIRRHOTIC PORTAL FIBROSIS
by immunologic abnormalities and a few other characteristic
diagnostic criteria as under: Non-cirrhotic portal fibrosis (NCPF) is a group of congenital
1. Female gender predisposition. and acquired diseases in which there is localised or
630 generalised hepatic fibrosis without nodular regenerative 10. Musculoskeletal abnormalities like digital clubbing,
activity and there is absence of clinical and functional hypertrophic osteoarthropathy and Dupuytren’s contracture
evidence of cirrhosis. Besides, the patients of NCPF are are more common in cirrhotic patients.
relatively young as compared to those of cirrhosis and 11. Endocrine disorders. In males these consist of feminisation
develop repeated bouts of haematemesis in the course of such as gynaecomastia, changes in pubic hair pattern,
disease. One of the types associated with increased portal testicular atrophy and impotence, whereas in cirrhotic
fibrosis without definite cirrhosis is seen in idiopathic women amenorrhoea is a frequent abnormality.
(primary) portal hypertension with splenomegaly, reported from 12. Hepatorenal syndrome leading to renal failure may occur
India and Japan. The type common in India, particularly in in late stages of cirrhosis.
young males, is related to chronic arsenic ingestion in drinking The ultimate causes of death are hepatic coma, massive
water and intake of orthodox medicines. It could also be due gastrointestinal haemorrhage from oesophageal varices
to portal vein thrombosis leading to intimal sclerosis of portal (complication of portal hypertension), intercurrent infections,
vein branches. Another variant is congenital hepatic fibrosis hepatorenal syndrome and development of hepatocellular
seen in polycystic disease of the liver. carcinoma.
MORPHOLOGIC FEATURES. Grossly, the liver is small,
fibrous and shows prominent fibrous septa on both PORTAL HYPERTENSION
external as well as on cut surface forming irregular islands Increase in pressure in the portal system usually follows
in the liver. obstruction to the portal blood flow anywhere along its
Histologically, the salient features are as under: course. Portal veins have no valves and thus obstruction
i) Standing out of portal tracts due to their increased anywhere in the portal system raises pressure in all the veins
amount of fibrous tissue in triad without significant proximal to the obstruction. However, unless proved
inflammation. otherwise, portal hypertension means obstruction to the
ii) Obliterative sclerosis of portal vein branches in the portal blood flow by cirrhosis of the liver. The normal portal
portal tracts (obliterative portovenopathy). venous pressure is quite low (10-15 mm saline). Portal
hypertension occurs when the portal pressure is above 30
CLINICAL MANIFESTATIONS AND mm saline. Measurement of intrasplenic pressure reflects
COMPLICATIONS OF CIRRHOSIS pressure in the splenic vein; the percutaneous transhepatic
pressure provides a measure of pressure in the main portal
The range of clinical features in cirrhosis varies widely, from vein; and wedged hepatic venous pressure represents
SECTION III
an asymptomatic state to progressive liver failure and death. sinusoidal pressure. Measurement of these pressures helps
The onset of disease is insidious. In general, the features of in localising the site of obstruction and classifying the portal
cirrhosis are more marked in the alcoholic form than in other hypertension.
varieties. These include weakness, fatiguability, weight loss,
anorexia, muscle wasting, and low-grade fever due to CLASSIFICATION. Based on the site of obstruction to
hepatocellular necrosis or some latent infection. Advanced portal venous blood flow, portal hypertension is categorised
cases develop a number of complications which are as into 3 main types—intrahepatic, posthepatic and prehepatic
follows: (Table 21.10). Rare cases of idiopathic portal hypertension
1. Portal hypertension and its major effects such as ascites, showing non-cirrhotic portal fibrosis are encountered as
splenomegaly and development of collaterals (e.g. discussed above.
oesophageal varices, spider naevi etc) as discussed below. TABLE 21.10: Major Causes of Portal Hypertension.
Systemic Pathology
2. Progressive hepatic failure and its manifestations as
described already (page 602). A. INTRAHEPATIC
3. Development of hepatocellular carcinoma, more often in 1. Cirrhosis
post-necrotic cirrhosis (HBV and HCV more often) than 2. Metastatic tumours
following alcoholic cirrhosis (page 634). 3. Budd-Chiari syndrome
4. Chronic relapsing pancreatitis, especially in alcoholic liver 4. Hepatic veno-occlusive disease
disease (page 646). 5. Diffuse granulomatous diseases
5. Steatorrhoea due to reduced hepatic bile secretion. 6. Extensive fatty change
6. Gallstones usually of pigment type, are seen twice more B. POSTHEPATIC
frequently in patients with cirrhosis than in general 1. Congestive heart failure
population. 2. Constrictive pericarditis
7. Infections are more frequent in patients with cirrhosis due 3. Hepatic veno-occlusive disease
to impaired phagocytic activity of reticuloendothelial system. 4. Budd-Chiari syndrome
8. Haematologic derangements such as bleeding disorders and
anaemia due to impaired hepatic synthesis of coagulation C. PREHEPATIC
factors and hypoalbuminaemia are present. 1. Portal vein thrombosis
9. Cardiovascular complications such as atherosclerosis of 2. Neoplastic obstruction of portal vein
coronaries and aorta and myocardial infarction are more 3. Myelofibrosis
frequent in cirrhotic patients. 4. Congenital absence of portal vein
1. Intrahepatic portal hypertension. Cirrhosis is by far the 631
commonest cause of portal hypertension. Other less frequent
intrahepatic causes are metastatic tumours, non-cirrhotic
nodular regenerative conditions, hepatic venous obstruction
(Budd-Chiari syndrome), veno-occlusive disease,
schistosomiasis, diffuse granulomatous diseases and
extensive fatty change. In cirrhosis and other conditions,
there is obstruction to the portal venous flow by fibrosis,
thrombosis and pressure by regenerative nodules. About 30-
60% patients of cirrhosis develop significant portal
hypertension.
2. Posthepatic portal hypertension. This is uncommon and
results from obstruction to the blood flow through hepatic
vein into inferior vena cava. The causes are neoplastic
occlusion and thrombosis of the hepatic vein or of the inferior
vena cava (including Budd-Chiari syndrome). Prolonged
congestive heart failure and constrictive pericarditis may also
cause portal hypertension by transmitting the elevated
pressure through the hepatic vessels into the portal vein.
3. Prehepatic portal hypertension. Blockage of portal flow
before portal blood reaches the hepatic sinusoids results in
prehepatic portal hypertension. Such conditions are
thrombosis and neoplastic obstruction of the portal vein
before it ramifies in the liver, myelofibrosis, and congenital
absence of portal vein.
MAJOR SEQUELAE OF PORTAL HYPERTENSION. CHAPTER 21
Irrespective of the mechanisms involved in the pathogenesis
of portal hypertension, there are 4 major clinical conse-
quences—ascites, varices (collateral channels or portosystemic Figure 21.30 Major clinical consequences of portal hypertension.
shunts), splenomegaly and hepatic encephalopathy (Fig. 21.30).
ii) Hyperaldosteronism. In cirrhosis, there is increased
1. Ascites. Ascites is the accumulation of excessive volume
of fluid within the peritoneal cavity. It frequently aldosterone secretion by the adrenal gland, probably due to
accompanies cirrhosis and other diffuse liver diseases. The reduced renal blood flow, and impaired hepatic metabolism
development of ascites is associated with haemodilution, and excretion of aldosterone.
oedema and decreased urinary output. Ascitic fluid is iii) Impaired renal excretion. Reduced renal blood flow and
generally transudate with specific gravity of 1.010, protein excessive release of antidiuretic hormone results in renal
content below 3 gm/dl and electrolyte concentrations like retention of sodium and water and impaired renal excretion.
those of other extracellular fluids. It may contain a few B. Local Factors:
mesothelial cells and mononuclear cells. Presence of i) Increased portal pressure. Portal venous pressure is not
neutrophils is suggestive of secondary infection and red directly related to ascites formation but portal hypertension
blood cells in ascitic fluid points to disseminated intra- in combination with other factors contributes to the formation The Liver, Biliary Tract and Exocrine Pancreas
abdominal cancer. However, some cases of ascites may and localisation of the fluid retention in the peritoneal cavity.
develop serious complication of spontaneous bacterial ii) Increased hepatic lymph formation. Obstruction of hepatic
peritonitis characterised by sponateneous infection of the vein such as in Budd-Chiari syndrome and increased intra-
ascitic fluid without any intrabdminal infection. sinusoidal pressure found in cirrhotic patients stimulates
Pathogenesis. The ascites becomes clinically detectable when hepatic lymph formation that oozes through the surface of
more than 500 ml of fluid has accumulated in the peritoneal the liver.
cavity. The mechanisms involved in its formation were 2. Varices (Collateral channels or Porto-systemic shunts).
discussed in Chapter 5. Briefly, the systemic and local factors As a result of rise in portal venous pressure and obstruction
favouring ascites formation are as under (Fig. 21.31): in the portal circulation within or outside the liver, the blood
A. Systemic Factors: tends to bypass the liver and return to the heart by
i) Decreased plasma colloid oncotic pressure. There is development of porto-systemic collateral channels (or shunts
hypoalbuminaemia from impaired hepatic synthesis of or varices). These varices develop at sites where the systemic
plasma proteins including albumin, as well as from loss of and portal circulations have common capillary beds. The
albumin from the blood plasma into the peritoneal cavity. principal sites are as under:
Hypoalbuminaemia, in turn, causes reduced plasma oncotic i) Oesophageal varices: The development of oesophago-
pressure and leads to loss of water into extravascular space. gastric varices which is frequently manifested by massive
632
Figure 21.31 Mechanisms of ascites formation in cirrhosis.
haematemesis is the most important consequence of portal However, metastatic tumours are much more common than
hypertension (page 539). primary tumours and tumour-like lesions. Primary hepatic
ii) Haemorrhoids: Development of collaterals between the tumours may arise from hepatic cells, bile duct epithelium, or
superior, middle and inferior haemorrhoidal veins resulting mesodermal structures (Table 21.11).
SECTION III
in haemorrhoids is another common accompaniment.
Bleeding from haemorrhoids is usually not as serious a TUMOUR-LIKE LESIONS
complication as haematemesis from oesophageal varices. These include cysts in the liver and focal nodular hyperplasia.
iii) Caput medusae: Anastomoses between the portal and
systemic veins may develop between the hilum of the liver Hepatic Cysts
and the umbilicus along the paraumbilical plexus of veins
resulting in abdominal wall collaterals. These appear as Cysts in the liver may be single or multiple. These cysts are
dilated subcutaneous veins radiating from the umbilicus and mainly of 3 types—congenital, simple (nonparasitic) and
are termed caput medusae (named after the snake-haired hydatid (Echinococcus) cysts.
Medusa). 1. CONGENITAL CYSTS. These are uncommon. They are
iv) Retroperitoneal anastomoses: In the retroperitoneum, usually small (less than 1 cm in diameter) and are lined by
Systemic Pathology
portocaval anastomoses may be established through the biliary epithelium. They may be single, or occur as polycystic
veins of Retzius and the veins of Sappey.
liver disease, often associated with polycystic kidney. On
3. Splenomegaly. The enlargement of the spleen in occasions, these cysts have abundant connective tissue and
prolonged portal hypertension is called congestive
splenomegaly (page 387). The spleen may weigh 500-1000
gm and is easily palpable. The spleen is larger in young TABLE 21.11: Classification of Primary Hepatic Tumours.
people and in macronodular cirrhosis than in micronodular Benign Malignant
cirrhosis.
A. Hepatocellular tumours
4. Hepatic encephalopathy. Porto-systemic venous Hepatocellular (liver cell) Hepatocellular (liver cell)
shunting may result in a complex metabolic and organic adenoma carcinoma
syndrome of the brain characterised by disturbed consci- Hepatoblastoma (Embryoma)
ousness, neurologic signs and flapping tremors. Hepatic B. Biliary tumours
encephalopathy is particularly associated with advanced Bile duct adenoma Cholangiocarcinoma
hepatocellular disease such as in cirrhosis. (Cholangioma) Combined hepatocellular and
cholangiocarcinoma
Cystadenocarcinoma
HEPATIC TUMOURS AND TUMOUR-LIKE LESIONS C. Mesodermal tumours
Haemangioma Angiosarcoma
The liver is the site for benign tumours, tumour-like lesions, Embryonal sarcoma
and both primary and metastatic malignant tumours.
numerous ducts, warranting the designation of congenital or may show slight variation in size and shape but no 633
hepatic fibrosis. mitoses. The hepatocytes in adenomas contain greater
2. SIMPLE (NON-PARASITIC) CYSTS. Simple cysts are amount of glycogen than the surrounding liver cells and
solitary non-parasitic cysts seen more frequently in middle- may sometimes show fatty change. Hepatocellular
aged women. The cyst is usually large (up to 20 cm in adenomas lack portal tracts and bile ducts but bile
diameter), lying underneath the Glisson’s capsule and filled canaliculi containing bile-plugs may be present.
with serous fluid. The cyst produces a palpable mass and Numerous blood vessels are generally present in the
may be associated with jaundice. tumour which may be thrombosed. Thrombosis leads to
infarction and may result in rupture with intraperitoneal
Histologically, the cyst wall is composed of compact haemorrhage.
fibrous tissue and is lined by low columnar to cuboid
epithelium and occasionally by squamous lining. Bile Duct Adenoma (Cholangioma)
3. HYDATID (ECHINOCOCCUS) CYSTS. Hydatid cyst Intrahepatic or extrahepatic bile duct adenoma is a rare
has already been discussed on page 616. benign tumour. The tumour may be small, composed of acini
lined by biliary epithelium and separated by variable amount
Focal Nodular Hyperplasia of connective tissue, or are larger cystadenomas having loculi
The etiology of focal nodular hyperplasia is not known but lined by biliary epithelium.
these lesions are more common in women taking oral
contraceptives. Haemangioma
Haemangioma is the commonest benign tumour of the liver.
Grossly, Focal nodular hyperplasia is a well-demarcated Majority of them are asymptomatic and discovered
tumour-like nodule occurring underneath the Glisson’s incidentally. Rarely, a haemangioma may rupture into the
capsule. The nodules may be single or multiple, peritoneal cavity.
measuring about 5 cm in diameter. It may be tan-yellow
or bile-stained. The sectioned surface shows a central MORPHOLOGIC FEATURES. Grossly, haemangiomas CHAPTER 21
fibrous scar. appear as solitary or multiple, circumscribed, red-purple
Histologically, it is composed of collagenous septa lesions, commonly subcapsular and varying from a few
radiating from the central fibrous scar which separate millimetres to a few centimetres in diameter. They are
nodules of normal hepatocytes without portal triads or commonly cavernous type giving the sectioned surface a
central hepatic veins. The fibrous septa contain prominent spongy appearance.
lymphocytic infiltrate. Histologically, haemangioma of the liver shows
characteristic large, cavernous, blood-filled spaces, lined
by a single layer of endothelium and separated by
BENIGN HEPATIC TUMOURS
connective tissue (Fig. 21.32). Some haemangiomas
These are uncommon and some of them are incidental may undergo progressive fibrosis and may later get
autopsy findings. These include hepatocellular (liver cell) calcified.
adenoma, bile duct adenoma (cholangioma) and
haemangioma. MALIGNANT HEPATIC TUMOURS
Hepatocellular (Liver Cell) Adenoma Among the primary malignant tumours of the liver, The Liver, Biliary Tract and Exocrine Pancreas
hepatocellular (liver cell) carcinoma accounts for approxi-
Adenomas arising from hepatocytes are rare and are reported mately 85% of all primary malignant tumours,
in women in reproductive age group in association with use cholangiocarcinoma for about 5-10%, and infrequently mixed
of oral contraceptives, sex hormone therapy and with pattern is seen. The remainder are rare tumours that include
pregnancy. The tumour presents as intrahepatic mass that hepatoblastoma, haemangiosarcoma (angiosarcoma) and
may be mistaken for hepatocellular carcinoma and may embryonal sarcoma. Hepatic haemangiosarcoma and
rupture causing severe intraperitoneal haemorrhage. embryonal sarcoma resemble in morphology with their
counterparts elsewhere in the body.
MORPHOLOGIC FEATURES. Grossly, the tumour
usually occurs singly but about 10% are multiple. It is Hepatocellular Carcinoma
partly or completely encapsulated and slightly lighter in
colour than adjacent liver or may be bile-stained. The Hepatocellular carcinoma (HCC) or liver cell carcinoma, also
tumours vary from a few centimetres up to 30 cm in trmed as hepatoma, is the most common primary malignant
diameter. On cut section, many of the tumours have tumour of the liver. The tumour shows marked geographic
varying degree of infarction and haemorrhage. variations in incidence which is closely related to HBV and
Histologically, liver cell adenomas are composed of sheets HCV infection in the region. Whereas the prevalence of HCC
and cords of hepatocytes which may be normal-looking is less than 1% of all autopsies in the United States and
Europe, the incidence in sub-Saharan Africa and South-East
634
Figure 21.32 Cavernous haemangioma of the liver.
Asia (particularly China) is high (2-8%). Liver cell cancer is iv) It is also possible that HBV and HCV infection act
more common in males than in females in the ratio of 4:1. synergistically to predispose to HCC.
The peak incidence occurs in 5th to 6th decades of life but in 3. Relation to cirrhosis. Cirrhosis of all etiologic types is
high incidence areas where HBV and HCV infection is more commonly associated with HCC but the most frequent
prevalent, it occurs a decade or two earlier. The tumour association is with macronodular post-necrotic cirrhosis. The
supervenes on cirrhosis in 70-80% of cases. mechanism of progression to HCC appears to be chronic
regenerative activity in cirrhosis, or that the damaged liver
ETIOPATHOGENESIS. A number of etiologic factors are in cirrhosis is rendered vulnerable to carcinogenic influences.
implicated in the etiology of HCC, most important being HBV
Liver cell dysplasia identified by cellular enlargement, nuclear
SECTION III
and HCV infection, and association with cirrhosis.
hyperchromatism and multinucleate cells, is found in 60%
1. Relation to HBV infection. Genesis of HCC is linked to of cirrhotic livers with HCC and in only 10% of non-cirrhotic
prolonged infection with HBV. The evidence in support is livers.
both epidemiologic and direct. 4. Relation to alcohol. It has been observed that alcoholics
i) The incidence of HBsAg positivity is higher in HCC have about four-fold increased risk of developing HCC. It is
patients. For example, in Taiwan, HBsAg-positive carriers possible that alcohol may act as co-carcinogen with HBV or
have more than 200 times greater risk of developing HCC HCV infection, but alcohol does not appear to be a hepatic
than HBsAg-negative patients, particularly when the carcinogen per se.
infection is acquired in early life. 5. Mycotoxins. An important mycotoxin, aflatoxin B1,
ii) In African and Asian patients, 95% cases of HCC have produced by a mould Aspergillus flavus, can contaminate
anti-HBc. poorly stored wheat grains or groundnuts, especially in deve-
Systemic Pathology
iii) There is more direct evidence of integration of HBV-DNA loping countries. Aflatoxin B1 is carcinogenic; it may act as
genome in the genome of tumour cells of HCC. a co-carcinogen with hepatitis B or may suppress the cellular
2. Relation to HCV infection. Long-standing HCV infection immune response.
has emereged as a major factor in the etiology of HCC, 6. Chemical carcinogens. A number of chemical carci-
generally after more than 30 years of infection. The evidences nogens can induce liver cancer in experimental animals.
in support are as under: These include butter-yellow and nitrosamines used as
i) In developed countries where higher incidence of HCC common food additives.
was earlier attributed to endemic HBV infection (e.g. in 7. Miscellaneous factors. Limited role of various other
Japan) has shown a remarkable shift to HCV infection. factors in HCC has been observed. These include the
However, in developing countries HBV is still the following:
predominant etiologic factor in the pathogenesis of HCC. i) haemochromatosis;
ii) The patients having anti-HCV and anti-HBc antibodies ii) α-1-antitrypsin deficiency;
together have three times higher risk of developing HCC than iii) prolonged immunosuppressive therapy in renal
in those with either antibody alone. transplant patients;
iii) HCV infection after a long interval produces cirrohosis iv) other types of viral hepatitis;
more often prior to development of HCC, while in HCC v) tobacco smoking; and
following HBV infection half the cases have cirrohosis and vi) parasitic infestations such as clonorchiasis and
remainder have chronic hepatitis. schistosomiasis.
The words you are searching are inside this book. To get more targeted content, please make full-text search by clicking here.
Discover the best professional documents and content resources in AnyFlip Document Base.
Search
Textbook of Pathology, 6th Edition
- 1 - 50
- 51 - 100
- 101 - 150
- 151 - 200
- 201 - 250
- 251 - 300
- 301 - 350
- 351 - 400
- 401 - 450
- 451 - 500
- 501 - 550
- 551 - 600
- 601 - 650
- 651 - 700
- 701 - 750
- 751 - 800
- 801 - 850
- 851 - 900
- 901 - 949
Pages: