2. Introduction:
Results from different mechanisms that lead to necroinfl
ammation & fibrogenesis.
Histologically: diffuse nodular regeneration surrounded by
dense fibrotic septa with subsequent parenchymal
extinction & collapse of liver structures, together causing
pronounced distortion of hepatic vascular architecture,
resulting in increased resistance to portal blood flow
causing portal hypertension &hepatic synthetic
dysfunction.
Clinically, cirrhosis regarded as an end-stage disease that
invariably leads to death, unless liver transplantation is
done&the only preventive strategies have been screening
for oesophageal varices & HCC.

3. Introduction:
But , 1-year mortality in cirrhosis varies widely, from 1-
57%, depending on the clinical decompensating events.
Histopathologists: cirrhosis should be substituted by
advanced liver disease, to underline the dynamic
processes& variable prognosis , since, fibrosis, even in the
cirrhotic range, regresses with specific therapy if available,
such as antiviral treatment for chronic hepatitis B or C.

4. Introduction:
It is the 14th most common cause of death in adults
worldwide & 4th in central Europe.
Cirrhosis is the main indication for 5500 liver transplants
each year in Europe.
The main causes in more developed countries are
infection with hepatitis C virus, alcohol misuse,
&increasingly, non-alcoholic liver disease.
infection with hepatitis B virus is the most common cause
in sub-Saharan Africa & most parts of Asia.
Prevalence is difficult to assess& higher than reported,
because initial stages are asymptomatic &undiagnosed.
Prevalence 0.3% in a French screening programme.

6. Diagnosis:
Most CLD is notoriously asymptomatic until clinical
decompensation occurs.
Decompensating include ascites, sepsis, variceal bleeding,
encephalopathy&non-obstructive jaundice.
Imaging by U/S, CT, or MRI of an irregular/nodular liver with
impaired liver synthetic function is sufficient for diagnosis.
Other findings include small shrunken liver, splenomegaly,
&evidence of portosystemic collaterals.
A liver biopsy is seldom needed but can provide a definitive
diagnosis & confirm the aetiology in cases of uncertainty.
The transjugular approach yields samples of equal quality to the
percutaneous one, is safe& adds additional prognostic
information through (HVPG) measurement.

7. Diagnosis:
In early cirrhosis, conventional imaging can be false-
negative diagnosis so other strategies are
Non-invasive markers of fibrosis are increasingly used;
they are more informative at the extremes of the liver fi
brosis range—ie, little or no fibrosis& cirrhosis.
They include indirect serum markers (simple, widely
available indices), direct serum markers that measure
biomarkers of fibrosis&imaging modalities, such as
transient elastography
These tests should be used 7 interpreted only once the
aetiology is known.

8. Diff Diagnosis:
Cong hepatic fibrosis (fibrosis without regenerative
nodules). Nodular
Regenerative hyperplasia (nodules but no fibrosis).
Non-cirrhotic portal hypertension.

15. Natural course& prognosis:
It is no longer a terminal disease & but a dynamic process.
A prognostic clinical subclassification with 4 distinct stages with
differing mortality:
Stage 1 (compensated with no EV) mortality of 1% / year.
Stages 2 (compensated with varices), 3.4%
Stage 3 (decompensated with ascites) 20%
Stage 4 (decompensated with GIB) 57
Stage 5 (Infections & renal failure) 67% 1-year mortality.
Acute decompensating with organ failure have mortality of
30%; notably higher in previously compensated.
Decompensating events are generally triggered by precipitating
factors as infection, PVT, surgery, HCC.

16. Natural course& prognosis:
Semiquantitative histological subclassification based on
nodular size & septal width is associated with HVPG &
clinical outcomes.
Subclassification based on quantitative fibrosis
assessment with collagen proportionate area in liver tissue
is also associated with HVPG & clinical outcomes is a
promising.
Non-invasive fibrosis markers, such as Fibroscan,
Fibrotest& ELF, are increasingly being used as prognostic
markers& should ideally be compared with those of semi
quantitative or quantitative histological methods to
subclassify cirrhosis.

17. Natural course& prognosis:
For patients with more advanced disease:
The MELD score is based on creatinine& bilirubin &(INR); it
predicts 3-month mortality.
UKELD adds serum sodium to the MELD predicts 1-year
mortality.
The Child-Pugh score is based on bilirubin , albumin, INR, &the
presence and severity of ascites & encephalopathy.

18. Prevention / treatment of complications:
Objectives: diagnose CLD as early as possible& prevent
the progression to further clinical stages & complications.
Population screening.
Lifestyle changes & general measures.
Cause-specific treatments.
Portal hypertension, varices& variceal bleeding.
Ascites. Infection.
Encephalopathy. HCC.

19. Population screening:
Screening for chronic HCV is cost effective.
Non-invasive fibrosis markers could be screening tools in
primary care, especially for NAFLD& for alcohol misusers.
The NAFLD fibrosis scores for NAFLD is based on simple
indices (age, platelet count,s.albumin, ALT,DM) has a
negative predictive value of 96% for advanced fibrosis.
More complex blood tests to class patients in the
community into three prognostic groups to rationalise
secondary referrals.
Transient elastography, now licensed in the USA, has also
been used to classify patients.

20. Lifestyle changes & general measures:
Lifestyle advice should be offered to all patients.
Insulin resistance, obesity, metabolic syndrome are
pathophysiologically linked with NAFLD, but they have
deleterious effects irrespective of liver disease aetiology.
Obesity is an independent predictor of cirrhosis in alcoholic liver
disease&metabolic syndrome is associated with more severe
fibrosis& cirrhosis in CLD.
Insulin resistance,DM,MetS predicts HCC in cirrhosis.
Overweight patients with compensated cirrhosis (clinical stages
I & II) should be advised to lose weight to lower long-term risk
of liver complications.

21. Lifestyle changes & general measures:
In patients with decompensated cirrhosis, maintenance of
adequate nutrition is important to avoid loss of muscle mass&
Such patients have low tolerance to long-term fasting, with
early onset of gluconeogenesis& subsequent muscle depletion,
which can also contribute to development of hepatic
encephalopathy.
All patients with cirrhosis irrespective of clinical stage should be
advised to abstain from alcohol& Multidisciplinary alcohol care
teams can lower the risk of acute hospital admission &improve
the quality of care.
In many centres, abstinence irrespective of liver disease
aetiology is mandatory for the patient to be considered for liver
transplantation.

22. Lifestyle changes & general measures:
Vaccination against hepatitis A and B viruses, influenza
virus,pneumococcus should be offered as early as possible,
because the antigenic response becomes weaker as cirrhosis
progresses.
Cigarette smoking is associated with more severe fibrosis in
chronic HCV, NAFLD, PBC &increases the risk of HCC in
chronic hepatitis B.
Cannabis use worsens fibrosis in chronic HCV.
Smoking cessation therefore should be advocated to prevent
progression of liver disease &facilitate eligibility for liver
transplantation.
Smoking increases post-transplant morbidity/ mortality.

23. Lifestyle changes & general measures:
Antioxidant-rich foods and drinks have a potential
preventive role in cirrhosis.
2 Cups /day Coffee improves all-cause mortality
&associated with a significant reduction in fibrosis in liver
disease of various causes& with reduced risk of HCC.
Ingestion of dark chocolate/Vit C, blunted the post-prandial
HVPG increase in cirrhosis by improving fl ow-mediated
hepatic vasorelaxation& ameliorated systemic
hypotension.
Physicians should always bear in mind drug interactions&
the possible need for dose reductions when prescribing for
patients with cirrhosis.

24. Cause –specific treatments:
Patients with cirrhosis should be treated when possible for
the underlying liver disease to stop disease progression.
Immuno suppression for AIH, venesection for
haemochromatosis & copper chelators or zinc for Wilson.
All patients with cirrhosis who are positive for HBsAg
should receive oral antiviral therapy with a potent antiviral
(entecavir or tenofovir) irrespective of viral load.
Oral antiviral reduces HVPG53 &delays clinical
progression to decompensation in responders.
Treatment with tenofovir for 5 years resulted in regression
of cirrhosis associated with hepatitis B.

25. Cause –specific treatments:
HCV-related cirrhosis without ascites, SVR significantly
reduced liver-related morbidity /mortality&in subgroups,
regression of cirrhosis.
This strategy is also valid for patients with HCV listed for
liver transplantation because of HCC rather than
complications of portal hypertension, because
achievement of SVR reduces post-transplant recurrence of
hepatitis C, which is otherwise universal.
Supplementary strategies include weight loss in obese,
vitD suppl when low, statins in DM & coffee drinking.
Patients with cirrhosis who respond to antivirals still need
regular surveillance for HCC, because the risk, although
reduced, is not eliminated.

26. Portal HT, varices& variceal bleeding:
PHT, rather than hepatocyte failure per se, is the underlying
cause of most of the complications of cirrhosis
&subsequent mortality.
HVPG is a good surrogate marker of PHT& has robust
prognostic power.
PHT is present when the HVPG is >5 mm Hg.
Clinically significant PHT&the threshold for development of
oesophageal varices is>10 mm Hg.
HVPG <10 mm Hg there is 90% probability of not
progressing to decompensation 4 years, while HVPG of >
10 mm Hg, the incidence of HCC *6 higher than in patients
with lower HVPG.

27. Portal HT, varices& variceal bleeding:
Eso varices is the first clinically relevant consequence of
portal hypertension&represents clin stage 2 of cirrhosis.
All patients with cirrhosis should be screened for varices
The risk of development &growth of varices is 7%/ year&
that of first variceal bleeding is 12% / year.
Pre-primary, primary&secondary prophylaxis strategies to
prevent variceal bleeding are available.
Trt options include nonselectiveβ blockers for varices,
irrespective of size, or EBL for medium or large varices.
Timolol for preprimary prevention of varices formation did not
show significant benefi t.

28. Portal HT, varices& variceal bleeding:
Primary prophylaxis of variceal bleeding should be offered
to all patients with varices, especially those that are large
or have red signs.
NSBB &EBL are equally effective in prevention of
bleeding&reduction of mortality.
NSBB decrease CO ,cause splanchnic vasoconstriction
reducing portal inflow, decrease azygous vein blood flow&
variceal pressure> the reduced portal inflow& reduce total
effective vascular compliance.
NSBB are titrated to the maximum tolerated dose, aiming
at a HR< 60 bpm, Side-effects of fatigue, hypotension,
shortness of breath preclude their use in 15–20&
specialised nurse-led clinics help to minimise withdrawal
&enable successful dose titration.

29. Portal HT, varices& variceal bleeding:
Carvedilol is BB with vasodilating properties resulting from
α1-blockade; it decreases intrahepatic vascular resistance,
which leads to a greater fall in HVPG than with
conventional non-selective BBs.
Carvedilol was more effective than EBL for primary
prophylaxis of bleeding,it is titrated against BP&HR up to
doses of 25 mg/day, because no greater reduction in HVPG is
achieved with higher doses.
We advocate use of NSBB as primary prophylaxis, because
they are cheap, effective, safer, no need for the expertise
,prevent bleeding from PHT gastropathy& have other beneficial
effects.

30. Portal HT, varices& variceal bleeding:
Simvastatin lowered HVPG& improved liver
haemodynamics in patients with cirrhosis&varices additive
NSBB,significantly reduce the incidence of HCC among
patients with diabetes,not associated with an increased
risk of hepatotoxicity in cirrhosis, given to patients with
cirrhosis&hyperlipidaemia.
Trials in non-hyperlipidaemic patients are in progress.

33. Infection in CLD:
Inf increases mortality *4 with poor prognosis, with 30%
dying within a month& another 30% within a year.
Most frequently SBP,UTI,pneumonia, skin infections;
incidence increases with worsening liver function.
Cases: Decreased bowel motility, bacterial overgrowth, ,
increased intestinal permeability.
NSBB reduced the incidence of SBP in patients with ascites, by
increasing bowel motility (so decreasing bacterial
translocation)& improve intestinal permeability independent of
the haemodynamic response.

34. Infection in CLD:
Primary prophylaxis of SBP with norfloxacin improves
survival in patients with advanced cirrhosis or impaired
renal function& low ascites protein concs (<15 g/L).
Since the risk of infections with quinolone-resistant
bacteria is high, we advocate primary prophylaxis only in
patients listed for liver transplantation.
Secondary prevention with oral quinolones should be off
ered to all patients with a previous episode of SBP.
No best strategy for prevention, if SBP with quinolone-
resistant organisms develops, has been established;
available options include no prophylaxis or a rolling
scheme of antibiotics.

35. Infection in CLD:
SBP is diagnosed if ascitic neutrophil is > 250 per μL & can
be asymptomatic.
Treatment consists of IV antibiotics & human albumin.
The choice of antibiotics is influenced by previous
quinolone prophylaxis, local prevalence of bacterial
strains& whether the infection was acquired in the
community or in hospital.
A 5-day course of IV cefotaxime is generally sufficient in
most community-acquired cases.
IV albumin (1.5 g/kg on day 1& 1.0 g/kg on day 3) lowers
the risk of renal impairment& death from 30- 10%.
PPI should be avoided except if PU bleeding.

36. Hepatic encephalopathy:
Is an ominous sign with 1-year mortality rate is up to 64%.
Encephalopathy despite preserved liver function should be
screened for spontaneous portosystemic shunts& embolisation
of large shunts is safe & effective in selected
Overt encephalopathy is generally transient& linked with
precipitating events:s edatives, constip, dehydration, inf, or GIB.
Lactulose is 1st-choice for prv of recurrent encephalopath
L-ornithine-l-aspartate is equivalent to lactulose.
Rifaximin, a nonabsorbable antibiotic, is effective when added
to lactulose if encephalopathy recurs; it reduces the risk of
further recurrence from 46- 21%.

37. Subclin( Minimal) HE:
Is more common than overt encephalopathy& influences
complex cognitive or coordination skills such as driving,
leading to increased risks of accidents& falls.
Cirrhotics who drive should be screened for MHE &treated
with lactulose if necessary.
Rifaximin significantly improved driving simulation skills
,but it is not currently cost effective.

42. Hepatocellular carcinoma
Guidelines recommend 6-monthly U/S screening.
HCC can develop in all stages of cirrhosis, of all causes.

43. Liver transplantation
In patients who develop decompensation or HCC.
The most commonly used scores are MELD in the USA ,
UKELD in the UK.

44. Future therapies
Statins, oral antibiotics, anticoagulants are likely to be used in
various combinations to prevent/ treat complications of
cirrhosis in the near future.
Statins reduce HVPG &reduced incidence of HCC.
Stable cirrhosis is characterised by normal thrombin
generation& even hyper coagulability.
Currently, anticoagulation is considered only in patients with
PVT awaiting liver transplantation,but it is associated not only
with lower risk of PVT, but also with delayed decompensation
& improved survival.
A surgically implanted pump transferring ascites to the bladder
has been tested for refractory ascites.

45. Future therapies
Rifaximin is a potential alternative for prevention of
spontaneous bacterial peritonitis
Metformin was independently associated with reduced
incidence of HCC.