Liver biopsy

LIVER BIOPSY PREFERRED INVESTIGATION FOR DIAGNOSIS OF

INFLAMMATION AND STAGE OF FIBROSIS IN CHRONIC LIVER DISEASEMEHNAAZ SULTAN KHUROOCONSULTANT PATHOLOGIST

GOVERNMENT MEDICAL COLLEGE SRINAGAR, J&K

GLOBAL IMPACT OF LIVER DISEASELiver disease is a major cause of illness and death worldwideChronic liver disease and cirrhosis are important causes of morbidity and mortality in the world.

Globally, alcohol consumption, hepatitis B (HBV) and hepatitis C (HCV) have been the main causes of cirrhosis.

However, increasing prevalence of OBESITY and the METABOLIC SYNDROME has resulted in increasing incidence of cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD), especially in developed countries.

Burden of chronic liver disease is projected to increase, due to, the increasing prevalence of end-stage liver disease and HCC secondary to NAFLD and HCV.

LIVER BIOPSY

Erlich is credited with the first liver aspiration in 1883

First percutaneous liver biopsy for diagnostic purposes was reported in 1923.

The technique has been modified since then.Over the past 50 years has become a central investigation of hepatic disease.

Low mortality (0.01-0.17%) and low morbidity of this procedure have meant that liver biopsy has become widely used.

LIVER BIOPSYLiver biopsy for long has been considered as an invaluable tool for diagnosis, prognosis and assessment of response to antiviral therapy.

It helps in quantification of necrosis, inflammation, fibrosis and fatwhich is of utmost importance in studying the progression of chronic liver disease

Newer/ non invasive modalities are competing to replace liver biopsy….none has been completely standardised and optimised to replace the “GOLD STANDARD”

• DIAGNOSIS• PARENCHYMAL LIVER DISEASE• ABNORMAL LIVER FUNCTION TESTS• FEVER OF UNKNOWN ORIGIN• FOCAL OR DIFFUSE ABNORMALITIES ON IMAGING

• PROGNOSISSTAGING OF KNOWN PARENCHYMAL LIVER DISEASE

Grading degree of Inflammation Staging degree of fibrosis Define risk for future decompensation Identify patients at risk for HCC

• MANAGEMENT• DEVELOPING TREATMENT PLANS BASED ON HISTOLOGIC ANALYSIS• Assess response to treatment

LIVER BIOPSY INDICATIONS

USE OF LIVER BIOPSY IN CLINICAL PRACTICEDIAGNOSIS STAGING PROGNOSIS MANAGEMENT

Hepatitis B + + + + + + + +Hepatitis C + + + + + + ++++Hemochromatosis + + + + + + + +Wilsons Disease ++ + + + + + _A1-AT + + + + ++ +AIH +++ + + + + ++ + +PBC ++ + + + + +++ + +PSC ++ + _ +Alcohol ++ +++ ++ +NAFLD/NASH ++ ++ ++ +HCC ++ - - + + + +Other focal lesions ++ ++Infiltrative ++++ ++ + ++DILI ++ - - - -ALF ++ - - - ++POST OLTX ++++ +++ ++ ++++

LIVER BIOPSYGRADING AND STAGING SYSTEM FOR

NECROINFLAMMATORY SCORES AND FIBROSIS Ishak modification for hepatic activity index (HAI) for scoring of necro-inflammatory activity in chronic hepatitis

Scheuer classification for grading and staging of chronic hepatitis

Metavir classification for staging of hepatitis C liver disease

Batts–Ludwig

International Association for Study of liver (IASL)

MEASUREMENT OF LIVER FIBROSISSirius red stains most hepatic collagens, (including types I & III, which are the main types involved in liver fibrosis).

Sirius red staining correlates with chemical hydroxyproline assays for collagen under standardised conditions.

Specific staining of biopsies for collagen with interactive image analysis provides specific, precise (sensitive) numerical information about liver fibrosis.

Smaller biopsy is associated with greater sampling error

Error reduced by increasing sample size and number of biopsies performed

Study found 25 mm biopsy had error rate of 25%

Optimal size 30-40 mm

But only 16% of samples are >20 mm

LIVER BIOPSY ADEQUACY

LIVER BIOPSY IN HIV/ HCV Assessment of liver histology may be particularly beneficial in patients with HIV and HCV

These patients have persistently normal ALT levels and may have significant fibrosis; which may be of prognostic importance

This allows clinicians to determine extent of fibrosis and consequently assess suitability for treatment

• DONOR SELECTION• One of the adverse impacts of the world epidemic of obesity/MS is the limited availability of suitable

donors. • Studies showed that steatosis of 30% (15% in LDLT) are not accepted and carries the danger of early

graft loss. ??? fibrosis• Studies showed that biopsy is the gold standard in assessing donor’s steatosis

• POST TRANSPLANT--- FATE OF EXPLANT• Assessment for Rejection—Acute/ Chronic• PROGRESSION of fibrosis (especially in HCV patients)

There is a poor correlation between serological liver tests and liver histology, and there is no accurate non-invasive method for differentiating HCV from rejection till now

LIVER BIOPSY IN TRANSPLANT SETTING

LIVER BIOPSYCONS

Invasive

Risk of complications 1-5%

• Mortality .01% to 0.1%

Limitations

• Sampling error

• Intra-observer variability

PROSSteatosis assessment and quantification

Fibrosis assessment and architectural distortion

Iron level measurement

Diagnose other pathology• Using special stains• other liver disease (viral hepatitis + NAFLD,

etc)

NON INVASIVE TESTS FOR ASSESING FIBROSIS/ INFLAMMATION/ FAT

• IMAGING TECHNIQUES•USG•CT•MRI/E•Hepatic elastography

•SERUM BIOMARKERS• Indirect•Direct

SERUM MARKERS OF FIBROSIS

IDEAL BIOMARKER

Liver specific

Independent of metabolic alterations

Detect fibrosis regardless of cause

Sensitive enough to distinguish between fibrosis stages

Reflective of dynamic changes

NEWER MODALITIES OF ASESSING LIVER FIBROSIS/ INFLAMMATION

TEST DISADVANTAGES ADVANTAGES

SERUM MARKERSDirect None of these markers are liver specific and are influenced

by metabolismNon invasive

Indirect • Not sensitive enough to distinguish between stages

• Degree of fibrosis does not linearly correlate with biopsy stage

• May be better to evaluate for inflammation (i.e., FibroTest)

• NON SPECIFIC FOR LIVER

• Influence of several extra-hepatic factors

Non Invasive

TEST DISADVANTAGES ADVANTAGES

IMAGING MODALITIES

USG Very low sensitivity and negative predictive value High specificity, Non invasive

TE Poor performance in mild to moderate diseaseCannot be used in Patients with ascitesMorbid obesity (BMI>40)CostCannot distinguish between stage 0-II or III-IV

Non Invasive

MRE Increased exposure time---60 minutes Can be performed in obese patientsHigher diagnostic accuracy

ARFI (Acoustic radiation force imaging) Further studies needed in order to specify role of ARFI elastography for non invasive staging of liver fibrosis

Less time consumingSuccessful in obese patients

IMAGING MODALITIES OF ASESSING LIVER FIBROSIS

FIBROSCANNon-invasive

Able to assess a much larger proportion of the liver

Serial measurements to evaluate fibrosis progression

Poor performance in mild to moderate disease

Cannot be used in• patients with ascites• Morbid obesity (BMI>40)

Cost

Cannot distinguish between stage 0-II or III-IV

The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.

Degos F et al (the FIBROSTIC study) Journal of Hepatology (December 2010)

AASLD CONSENSUS STATEMENTS• Liver biopsy is currently a fundamentally important tool in the management of patients

with liver disease, important for diagnosis as well as staging of liver disease and its use is recommended until clearly superior methodologies are developed and validated (class IIB, level C)

• Liver biopsy is the 'gold standard' for diagnosis and follow up of fibrosis and implementing specific antiviral therapy.

• Protocol liver biopsy is of utmost importance in the post transplant care of patients. (1A)

• Transient elastography for replacing biopsy in the assessment and diagnosis of fibrosis progression still needs validation through large scale clinical studies. (2C)

• Biopsy is the gold standard for assessing the presence and degree of steatosis in the donor graft. (1C)

Rockey D et al. LIVER BIOPSY. Hepatology 2009