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Thursday, 13 July 2017

Regression of cirrhosis-my current understanding

* 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
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 pressure. 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-Garciawhere 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 area 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 technology. 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 cause. 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 human. 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 , 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
 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
 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

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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