*
Professor Department of Pathology;
Murshidabad Medical college ; Berhampore station road; Berhampore court ; Murshidabad
District ;West Bengal; India and Professor of Pathology(on
Deputation) Calcutta school of Tropical
Medicine ; 108 CR Avenue Kolkata-700073 West Bengal
**
Associate Professor, Dept of Pathology ,
Calcutta School of Tropical Medicine,
108, CR Avenue Kolkata -700073
West Bengal
*** of all
Residents 7/51 purbapalii sodepur 24 parganas north west Bengal India
**** Swamiji Nagar South Habra North 24
parganas West Bengal India
***** BK Mitra Palliative care institute Barrackpore North 24 parganas
West Bengal India
Corresponding authors
Pranab kumar Bhattacharya; MD ( University of
Calcutta) FIC path WBMES * Professor
Department of Pathology Murshidabad Medical college Berhampore
Murshidabad West Bengal India and Professor of Pathology Calcutta school of
Tropical Medicine ; 108 CR Avenue Kolkata-700073 West Bengal
Mobile- 9231510435
Copyright- Belongs to Professor Dr. Pranab Kumar Bhattacharya as per Copyright Laws of
IPR
Abstract
-:
The anatomical and
histo pathological state of chronic liver
diseases is a balance between the effects of liver injury and repair . As cirrhosis develops and progress the
fibrous bands tends to be thick and widened with evidence of histological activity and Cirrhosis is more of a macro nodular pattern . If
the cause of ensuing liver injury is removed or if effective
treatment of underlying liver
injury diseases are ensured , regeneration of hepatocytes dominates over
fibrosis resulting enlargement of regenerative nodules and
expansion against septae as well as lyses of sepate. Nodules surrounded by thin
sepate then coalesce
first giving rise to macro nodular pattern cirrhosis. Incomplete septal
cirrhosis is morphological land mark
in this dynamic process of regeneration
and repair and thus these
authors postulate that incomplete
cirrhosis is a feature of
regressing cirrhosis rather than a separate entity as it was told by Poper H etal in 1966
Keyword
Histopathological Sub classification of Cirrhosis; Regression of Cirrhosis,
Histological criteria of Regression of
cirrhosis, incomplete Cirrhosis
Introduction-
Cirrhosis is defined as a diffuse process characterized by fibrosis and the
conversion of normal liver architecture into structurally &functionally
abnormal nodule. A new patho physiological relevant definition of cirrhosis
state and cirrhosis is the collection of anatomic changes in the liver that
results from presence of wide spread imbalance of hepatic blood flow where
inflow exceeds the outflow capacity in cirrhosis fibrous septea develops when
there is formation of parechymal extinction lesions with loss of contagious
hepatocytes. Parenchymal extinction
lesions accumulates to form confluent regions of extinctions that results in
morphological pattern recognizable of cirrhosis. Activation of hepatic
fibroblasts is mediated mainly by inflammatory or congestive mechanism.
So Cirrhosis becomes the end stage of liver fibrosis and it
results from a variety of chronic liver insults we know, which includes,
congenital, metabolic, toxic, inflammatory and various infective causes and
cirrhosis leads to complete morphologic
alteration of liver and switch from lobular to a nodular organization
associated with vascular remodeling & biochemical changes
Clinical
Staging of Cirrhosis
Clinical Staging of Cirrhosis is based on the factors that
predict death. The utility of clinical sub classification is meant mainly for
identification of patients who will require liver transplant. Broadly
clinically Cirrhosis have been classified as I) compensated cirrhosis II) de-compensated
cirrhosis. Now de-compensated cirrhosis is defined by the clinically defected ascities,
varicial hemorrhage, hepatic
encephalopathy with jaundice and all these complications results from portal
hypertension and or liver cells functional insufficiency. The hepatic venous
pressure gradient (HVPG) is used for sub classification and predictor of poor
outcome. Advantage of HVPG is that a trans jugular liver biopsy can be obtained
during the same procedure, which can help histological & hemodynamic
correlations.
Histological sub-classification of Cirrhosis-
Though liver biopsy is an invasive procedure and mostly today replaced by
fibroscan, however it is still the gold standard for diagnose of liver
disorders, for staging of chronic liver diseases and for establishing the diagnosis.
Liver biopsy provides more information regarding patho physiology of the
diseases and has added advantages that it can be reviewed retrospectively.
Several histopathological features has
been evaluated to correlate with severity of chronic liver disease including
cirrhosis. The three features which are most important and significant are
nodule size, septal fibrosis / and width to correlate with clinical outcome.
With increasing severity of liver diseases, the amount of fibrosis increases
and parenchymal mass of hepatocytes decreases. Along similar liver, a reported
case of conversion from micronodular to
macronodular cirrhosis are associated with clinical improvement.
The Lannec group of expert liver pathologists first proposed classification of cirrhosis in
the following manner-based or nodule size and septal thickness ① ②
Stage-4a-: Definite or probable Cirrhosis, Thin Septa, 1(one)
broad septum can be allowed.
Stage-4b-: At least two(2) broad Septa, but no very broad
septum.
Stage-4c-: At least One( 1) very broad septum or many minute
nodules.
Septa are defined as broad when the thickness is equivalent
the size of the small module and as very broad septa when the thickness is
greater than the size of nodule.
Laennec system of
fibrosis & staging of cirrhosis correlated with not only HVPG but also with
severity of varies and ascities. In the Laennc system fibrosis septae are described as broad when the thickness is
equivalent to the size of the nodule and very thick when the thickness is
greater than the size of the nodule.
However Nagula et al sub-classified cirrhosis, when they did
study on chronic hepatitis C patients showed small nodules and thick septae were more likely to have HVPG greater than
10mm Hg pressure③. In their study they compared the size of the nodule to
width of liver biopsy and showed that small nodules were less than 1mm, large
nodules were greater than 2mm, thin septae were less than 0.2mm and thick septae were greater than 0.4mm and they devised a
scoring system to categorize cirrhosis into Category A and Category B, based on
nodule size and septal thickness.
Most Recent Classification system
The most
recent classification was done Jain-Garcia④ where the
histologic criteria had been better defined in more objective ways. The
Jain-Garcia system that their author followed
are based on different histological criteria to classify cirrhosis. For
classification of cirrhosis the type of predominant (>2/3 septa) or nodules in the biopsy is taken into
account to classify, otherwise considered as mixed as it is given below
Nodule Septa Score
Large Nodule (>2mm)=1 Thin
septae (<0.1mm)=3 <4(Stage-4a)
Mixed Nodules =2 Intermediate
septae (0.1-0.2mm)=2 4(Stage 4b)
Small Nodules (<1mm)=3 Thick
septae (>0.2mm)=4 >4(Stage4c)
Collagen proportionate is important in sub classifying chronic
liver disease for Hepatitis C patients
to be done with Elastic Vangesion Stain(EVG) Stain or Sirius stain . Fibrosis is
expressed as the area occupied by collagen
as a proportion of total biopsy area
referred as collagen proportionate area⑤ and collagen
proportionate area correlate well with clinically significant portal hypertension.
This procedure is done by these authors by Sirus Red Stained sections using computer
assisted digital imaging technology⑥. However crude assessment of
collagen can also be done by a well trained histopathologist in good in good bi ocular Microscope too.
Why this Sub Classification required?
There are evidences, both in
animal models and in human that liver fibrosis and even cirrhosis can be
regressed or completely revert to normal
liver architecture and function, either
on cessation of the cause of liver injury or treatment of the underlying cause⑥.
In 1979, there was a land mark published
paper in journal Pathology Annual by
Perez Tamzyao, who first described the
evidence for reversal of fibrosis and cirrhosis in both animal model and
in human⑦. They demonstrated first that arrest of fibrogenic stimulus can cause reversion of liver fibrosis
induced by CCl4 intoxications or bile duct ligation in rat models .
We today know that following antiviral treatment of hepatitis B, a shift from
fully developed hepatitis B induced cirrhosis
to incomplete septal cirrhosis . The best demonstration of such
reversibility of cirrhosis is demonstrated in patients with hepatitis C virus
(HCV) or hepatitis B virus (HBV) cirrhosis treated effectively with drug sofusbuvir( for genotypes 1, 2, 3, 4, 5, and 6)
or with velpatasvir , or with γ-interferon(peginterferon)
, . In additions there are also several
reports of histo pathological proof
(Stage 4c cirrhosis) in auto Immune hepatitis ⑧, hereditary heamochromotosis,
secondary briliary cirrhosis and occasional cases of wilson’s disease.
The morphological features of regressing cirrhosis in human
have been defined above. Regression of cirrhosis involves two main processes,
namely decrease in fibrosis and repopulation of fibrogenic region by
regenerating hepatocytes. There is not decrease of amount fibrous tissue and
collagen tissue which may be assessed by sinus red stain followed by computer
assisted digital images or by vangision stain and reticulin stain followed by
morphometric measurement of fibrous area. There will be thinning of fibrous
septa with disappearance of shunting vessels where the septa and septa becomes
incomplete gradually thinned out and finally disappear. Bile ductular proliferation
will disappear quickly in a regressing liver where as sinusoidal capillaries proliferation
and peri sinusoidal fibrosis become inconsistent regression of fibrosis is
associated with partial or full restoration lobular organization. There are
eight parameters which represent hepatic repair complex or regression of
cirrhosis. 1)Perforated delicate septa, 2)isolated thick collagen
fibers,3)delicate peri portal fibrous spikes,4) portal tract remnants,5)hepatic
vein remnants with prolapsed hepatocytes ,6)hepatocytes within portal tracts or
split septa.
A New Concept
of Incomplete Septal Cirrhosis
Histo pathologically
different pattern of Cirrhosis can be described which depends on interplay
between hepatocyte injury, regeneration
and fibrosis . Morhphologically Cirrhosis is usally termed Micronodular or macronodular or mixed
type . There is another type of Cirrhosis which was introduced
by Popper .H etal as incomplete septal cirrohosis(9) – a type
of macronodular cirrhosis
in which slender incomplete
septae demarcate larger inconspicuous nodules . On needle biopsy of liver apart from
then 1) incomplete septa render 2) a vague nodule
formation to the liver .
Incomplete Septal cirrohosis is also associated with 3) Hypoplastic Portal tract 4) Increase in venous chanels 5)
Abnormal spacing between portal
tracts and veins 6) Crowding of
Reticulin fibers between adjacent zones
of Hyperplastic Parenchyma 7) hepatocyte cell plate thickening 8) dilated Sinusiods
Regression of
Cirrohosis is best demonstrated in Chronic Hepatitis B and Chronic Hepatitis C
after effective treatment with drug sofusbuvir( for genotypes 1, 2, 3, 4, 5, and 6)
or with velpatasvir , with or without Ribavirin or with γ-interferon(peginterferon)
. Regression may be demonstrated also in Alcoholic cirrohosis in compensated state after abstinence of alcohol and with antifibrogenic drugs
Similarly Histopathological improvement beween pared liver biopsies is also observed after weight loss, hypocaloric diet, Blood
sugar control , control of hyperlipidimia
and exercise in established NASH
or NAFLD related cirrhosis . There are
many reports of regression of
cirrohosis in autoimmune hepatitis after treatment with Prednisilone and Azothiaprine
In contrast
features of regressions have not been yet well established in primary
billiary cirrhosis , primary sclerosing
cholangitis and vascular obliterative disease
Progression
versus Regression assessment by pathologists
As a pathologist while we authors evaluate liver biopsy from a case of established cirrhosis we must try to evaluate whether cirrhosis is
progressive or regressive as per Wanless criteria(10). This should
be assessed in paired liver biopsies taken after significant
time interval of complete treatment. A biopsy Length of at least 2-3 cm
or presence of 11 complete portal tract are considered adequate liver biopsy
for this purpose
General
|
Progression
|
Regression
|
Area
|
Enlarged with chronic inflammation &
fibrosis
|
Normal or enlarged , but with fibrosis only
|
Bile ducts
|
Preserved or absent
|
Usually preserved
|
Hepatic Artery
|
May be
prominent due to formation of vascular shunts
|
Prominence of hepatic arterioles persist
|
Portal veins
|
Obscured due to obliterative venopathy
|
Obscuring portal veins
|
Interface Activity
|
Frequently active interface hepatitis,
cholestasis , ductular proliferation
|
inactive
|
Fibrous Septa
|
With
or without bridging: Pattern of septal fibrosis depends on Etiology _: broad
inflamed septa in case of viral hepatitis
More delicate sinusoidal fibrosis in Alcohol,
Toxic and Metabolic conditions
|
Thinned delicate ( even bridging) may exhibit . Discontinuty ,Perforation
|
Parenchymal Hepatocytes
|
May or
may not show characteristic histological feature of Etiology
|
May be
residual feature of underlying cause present
|
Hepatic cellular complex
|
Absent
|
Present
|
References
①Kutami R, Girgrah N, Wanless IR etal. The Laennec grading
system for assessment of hepatic fibrosis: validation by correlation with
wedged hepatic vein pressure as clinical feature. Heptalogy 32:407A:2000
②Wanless IR,Sweeney G,Dhilon A.P etal “Lack of progressive
hepatic Fibrosis during long term therapy with deferiprone in subjects with
transfusion dependent Beta Malassemia Blood .” 100:1566-9:2002.
③Nagula S, Jain D, Groszmann R.J etal-
Histological-hemodynamic correlation in cirrhosis- a histological
classification of the severity of cirrhosis. J. Hepatol-44:177-7,2006
④Pierre Bedosa, Guadal Pepe-Garcia-Tsao, Dhanpat Jain
“Cirrhosis regression and Sub classification.” Surgical Pathology 6:295-309:2013
⑤Calvaruso V, Burroughs A.K, Standish R etal “computer
assessed Image analysis of Liver collagen: relationship to Ishak scoring and
hepatic venous pressure gradient” Heptalogy 49.1236-44:2009
⑥Friedman S.L, Bansal MB “reversal of hepatic fibrosis-
fact or fantasy? “ Hepatogy 43:82-88:2006
⑦Perez-Tamzyo R ”Cirrhosis of the Liver: a reversible
disease? “ Pathol.Annu 14(2):183-213 1979
⑧Czaja A.J, Carpenter HA. Decreased fibrosis during Cortico
Steroid Therapy of auto immune hepatitis. J.Hepatol 40:646-52:2004
(9) Poper H What is
the major types of Hepatic Cirrhosis In Ingelflinger F, Relman A ; Finland M Eds Controversy in Internal Medicine Philadelphia ,Publishers Saunders 1966 : 233-243
(10) Wanless I R , Nakashime E, Shirman M Regression of Human cirrhosis : Morphological Features and the genesis of incomplete septal cirrhosis Arch.Pathol. Lab. Med 12:1599-1607: 2000
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This article has been Published in International Clinical Pathology Journal (ICPJL)
Table of content and in htmlISSN: 2471-0016 Volume 5; Issue 2; 128-132 ; - 2017 Received: July 12, 2017 | Published: November 08, 2017 P 128_132
For Citation: Bhattacharya PK, Mukherjee S, Panda S, Bhattacharya R, Mukherjee D, et al. (2017) DOI: 10.15406/icpjl.2017.05.00128 URLhttp://medcraveonline.com/ICPJL/
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