chronic liver diseases

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CHRONIC LIVER CHRONIC LIVER DISEASES & PLCC DISEASES & PLCC Dr G.O OGUN Dr G.O OGUN Dept of Pathology Dept of Pathology College of Medicine College of Medicine University of Ibadan University of Ibadan 1

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Page 1: Chronic Liver Diseases

CHRONIC LIVER CHRONIC LIVER DISEASES & PLCCDISEASES & PLCC

Dr G.O OGUNDr G.O OGUNDept of PathologyDept of Pathology

College of MedicineCollege of MedicineUniversity of IbadanUniversity of Ibadan

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IntroductionIntroduction Is liver disease that persist over many Is liver disease that persist over many

months without progressive months without progressive improvement towards normalcy of improvement towards normalcy of usually the architecture.usually the architecture.

May follow acute disease with May follow acute disease with manifestation been insidious manifestation been insidious

Time interval- >6weeksTime interval- >6weeks The degree of hepatic dysfunction The degree of hepatic dysfunction

varies widely and can vary from varies widely and can vary from asymptomatic to symptomatic.asymptomatic to symptomatic.

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AETIOLOGYAETIOLOGY Chronic hepatitis+Chronic hepatitis+ Hepatic Cirrhosis+*Hepatic Cirrhosis+* SchistosomiasisSchistosomiasis Alcoholic liver diseaseAlcoholic liver disease Liver cell carcinoma+*Liver cell carcinoma+* HaemochromatosisHaemochromatosis Alpha-1-antitrypsin deficiencyAlpha-1-antitrypsin deficiency Wilson’s diseaseWilson’s disease Primary biliary cirrhosisPrimary biliary cirrhosis Chronic biliary obstructionChronic biliary obstruction*Hepatic cirrhosis and liver cell carcinoma are *Hepatic cirrhosis and liver cell carcinoma are

stages in liver damage common to many stages in liver damage common to many aetiologies.aetiologies.

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Chronic HepatitisChronic Hepatitis Is defined as symptomatic, biochemical or Is defined as symptomatic, biochemical or

serologic evidence of continuing or serologic evidence of continuing or relapsing hepatic disease for more than 6 relapsing hepatic disease for more than 6 months with histological documentation of months with histological documentation of inflammation and necrosis.inflammation and necrosis.

HBV,HCV and HBV+HDV are responsible for HBV,HCV and HBV+HDV are responsible for most chronic hepatitismost chronic hepatitis

Other aetiologies – Drugs- INH, alpha Other aetiologies – Drugs- INH, alpha methyl dopa, methotrexate and methyl dopa, methotrexate and autoimmunityautoimmunity

In all cases of chronic hepatitis, aetiology is In all cases of chronic hepatitis, aetiology is the single most important indicator of the single most important indicator of likelihood of progression to cirrhosis.likelihood of progression to cirrhosis. 44

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Viral Hepatitis: Viral Hepatitis: MicrobiologyMicrobiologyVirusVirus Hep-AHep-A Hep-BHep-B Hep-CHep-C

agentagent ssRNAssRNA dsDNAdsDNA ssRNAssRNA

Transm.Transm. Feco-Feco-oraloral

Parenteral, Parenteral, close contactclose contact

ParenteralParenteral, close , close contcont

Carrier Carrier statestate

NoneNone 0.1-1.0%0.1-1.0% 0.2-1.0%0.2-1.0%

Chronic Chronic HepatitisHepatitis

NoneNone 5-10% of acute 5-10% of acute infectioninfection

>50%>50%

HCCHCC NoNo YesYes YesYes55

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Hepatitis C Virus

The non-A, non-B factor 66

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Picture credit: http://www.info.gov.hk/hepatitis/images/fig07.gif 77

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HBVHBV Is a hardy virus and can survive extreme Is a hardy virus and can survive extreme

temperature and humidity.temperature and humidity. 350 million world wide carrier rate, 2 350 million world wide carrier rate, 2

billion of people alive has come in contact billion of people alive has come in contact with it. with it.

Blood and body fluid are primary sources Blood and body fluid are primary sources of infection- also- semen, saliva, sweat, of infection- also- semen, saliva, sweat, tears, breast milktears, breast milk

Vertical transmission from infected mother Vertical transmission from infected mother to neonate is common in Africa and Asia to neonate is common in Africa and Asia leading to carrier state for lifeleading to carrier state for life

Circulating host IgG antibodies neutralises Circulating host IgG antibodies neutralises HBV, vaccination has been highly effective HBV, vaccination has been highly effective in reducing the prevalence in endemic in reducing the prevalence in endemic areas of the world. e.g Taiwan example.areas of the world. e.g Taiwan example.

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Normal Liver - MicroscopyNormal Liver - Microscopy

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Chronic hepatitis - 2Chronic hepatitis - 2

Chronic viral hepatitis constitutes a “carrier” Chronic viral hepatitis constitutes a “carrier” state because the patient harbor replicating state because the patient harbor replicating virus and can transmit the organism.virus and can transmit the organism.

Patients can eitherPatients can either1.1. Habor the virus but suffers little or no Habor the virus but suffers little or no

adverse effect.adverse effect.2.2. Those with chronic hepatitis by laboratory Those with chronic hepatitis by laboratory

and histologic findings but are symptom freeand histologic findings but are symptom free3.3. Those with clinically symptomatic chronic Those with clinically symptomatic chronic

disease.disease.

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VirusesChronic Hepatitis C

Usually asymptomatic

• Route of infection– IV drugs (80%)

– Blood products

– Unknown

– Needle stick

– Vertical transmission

• Diagnosis– Hepatitis C Ab (IgG)

– HCV RNA

– ALT raised

• Complications– Chronic infection

– Cirrhosis

20% resolves spontaneously1212

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Chronic Hepatitis C

• Advise to patient– Alcohol < 10u/week

– Do not share razors

– Normal lifestyle

Infection

Cirrhosis

DecompensatedCirrhosis

Liver failure (death or transplant)

30 yrs

5-15yrs

1-2yrs Interferon/Ribavirin

55% cure

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Morphology - AcuteMorphology - Acute Tissue alteration caused by acute infection Tissue alteration caused by acute infection

with HAV,HBV,HCV,HEV are similarwith HAV,HBV,HCV,HEV are similar HBV- infected hepatocytes – ground glass HBV- infected hepatocytes – ground glass

appearance- due to spheres and tubules of appearance- due to spheres and tubules of HBsAg packed in the cytoplasm- appears HBsAg packed in the cytoplasm- appears eosinophilic.eosinophilic.

HCV- infected liver shows lymphoid aggregates HCV- infected liver shows lymphoid aggregates within the portal tract and sublobular within the portal tract and sublobular macrosteatosis.macrosteatosis.

Interphase hepatitis- Is when inflammation Interphase hepatitis- Is when inflammation spill over from the portal tract into adjacent spill over from the portal tract into adjacent parenchyma to cause necrosis of the periportal parenchyma to cause necrosis of the periportal hepatocytes – occurs in both acute and hepatocytes – occurs in both acute and chronic.chronic.

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MORPHOLOGY-ChronicMORPHOLOGY-Chronic In the mild forms, significant inflammation is In the mild forms, significant inflammation is

limited to the portal tract and consist of limited to the portal tract and consist of lymphocytes, macrophages, occasional plasma lymphocytes, macrophages, occasional plasma cells and rarely neutrophils and eosinophils.cells and rarely neutrophils and eosinophils.

In mild chronic HCV- lymphoid aggregates and In mild chronic HCV- lymphoid aggregates and bile duct damage in the portal tracts and mild bile duct damage in the portal tracts and mild to moderate macrovesicular steatosis.to moderate macrovesicular steatosis.

HBV- “Ground glass hepatocyte”, “sanded” HBV- “Ground glass hepatocyte”, “sanded” nucleinuclei

In all form of chronic hepatitis, continued In all form of chronic hepatitis, continued INTERPHASE hepatitis and BRIDGING INTERPHASE hepatitis and BRIDGING inflammation and necrosis are sign of inflammation and necrosis are sign of progressive liver damage.progressive liver damage.

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Morphology –Chronic -contdMorphology –Chronic -contd

The hallmark of irreversible liver The hallmark of irreversible liver damage is the deposition of fibrous damage is the deposition of fibrous tissue.tissue.

Initially affect only the portal tract, Initially affect only the portal tract, then periportal septal fibrosis, then then periportal septal fibrosis, then linkage of fibrous septal between linkage of fibrous septal between lobules ( bringing fibrosis.lobules ( bringing fibrosis.

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Acute viral Hepatitis:Acute viral Hepatitis:

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Acute viral Hepatitis:Acute viral Hepatitis:

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Acute viral Hepatitis:Acute viral Hepatitis:

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Liver Biopsy – viral Hepatitis-CLiver Biopsy – viral Hepatitis-C

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Liver Biopsy - CAH:Liver Biopsy - CAH:

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Liver Biopsy – CPH:Liver Biopsy – CPH:

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CIRRHOSISCIRRHOSIS

Is a chronic liver disease characterised byIs a chronic liver disease characterised by

1.1. Diffuse involvement of the liverDiffuse involvement of the liver

2.2. Complete loss and distruption of the Complete loss and distruption of the architecture of the liverarchitecture of the liver

3.3. Extensive bridging fibrous septae/fibrosisExtensive bridging fibrous septae/fibrosis

4.4. Regenerating parenchymal nodules with Regenerating parenchymal nodules with diameter varying from very small (<3mm, diameter varying from very small (<3mm, micronodules) to larger of several micronodules) to larger of several cm(Macro)cm(Macro) 2424

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CIRRHOSIS- 2CIRRHOSIS- 2

Cirrhosis is common end result of many Cirrhosis is common end result of many chronic liver disorders.chronic liver disorders.

Diffuse scarring of liver – follows Diffuse scarring of liver – follows hepatocellular necrosis of hepatitis.hepatocellular necrosis of hepatitis.

Inflammation – healing with fibrosis - Inflammation – healing with fibrosis - Regeneration of remaining hepatocytes Regeneration of remaining hepatocytes form regenerating nodules.form regenerating nodules.

Loss of normal architecture & function.Loss of normal architecture & function.

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CIRRHOSIS -3CIRRHOSIS -3 Vascular architecture is reorganized by Vascular architecture is reorganized by

the parenchymal damage and scarring the parenchymal damage and scarring with formation of abnormal with formation of abnormal interconnections between vascular interconnections between vascular inflow and hepatic vein outflow inflow and hepatic vein outflow channels thus portal and arterial blood channels thus portal and arterial blood by passes the liver.by passes the liver.

Fibrosis is key feature of progressive Fibrosis is key feature of progressive damage to the liverdamage to the liver

Once cirrhosis is established, it is usually Once cirrhosis is established, it is usually impossible to establish an aetiology on impossible to establish an aetiology on morphologic grounds alone.morphologic grounds alone. 2626

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Normal LiverNormal Liver

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CirrhosisCirrhosis

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Normal Liver HistologyNormal Liver Histology

CV

PT

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CirrhosisCirrhosis

Fibrosis

Regenerating Nodule

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AETIOLOGY OF CIRRHOSIS (OUR AETIOLOGY OF CIRRHOSIS (OUR ENVIRONMENT)ENVIRONMENT)

HBV infection (chronic) –high prevalence HBV infection (chronic) –high prevalence presumedpresumed

HCV,HDV (chronic)- high prevalence HCV,HDV (chronic)- high prevalence presumedpresumed

AlcoholicAlcoholic CryptogenicCryptogenic Hereditary, immunologic, metabolic- Hereditary, immunologic, metabolic-

alpha antitrypsin deficiency, alpha antitrypsin deficiency, Primary haemochromatosis, Wilsons disease, Primary haemochromatosis, Wilsons disease, galactosaemia, primary biliary cirrhosisgalactosaemia, primary biliary cirrhosis

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Aetiology of Cirrhosis ( Western Aetiology of Cirrhosis ( Western World)World)

Alcoholic liver diseaseAlcoholic liver disease 60-70%60-70% Viral hepatitisViral hepatitis 10%10% Biliary diseaseBiliary disease 5-10%5-10% Primary hemochromatosisPrimary hemochromatosis 5%5% Cryptogenic cirrhosisCryptogenic cirrhosis 10-15%10-15% Wilson’s, Wilson’s, 1AT def1AT def rarerare

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Pathogenesis:Pathogenesis: Hepatocyte injury leading to necrosis.Hepatocyte injury leading to necrosis.

– Alcohol, virus, drugs, toxins, genetic etc..Alcohol, virus, drugs, toxins, genetic etc.. Chronic inflammation - Chronic inflammation - (hepatitis).(hepatitis).

Bridging fibrosis.Bridging fibrosis. Regeneration of remaining hepatocytes Regeneration of remaining hepatocytes

Proliferating as round nodules.Proliferating as round nodules. Loss of vascular arrangement results in Loss of vascular arrangement results in

regenerating hepatocytes which are regenerating hepatocytes which are ineffective.ineffective.

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Pathogenesis-2Pathogenesis-2 Main source of collagen in cirrhosis is the Main source of collagen in cirrhosis is the

interstitial cells of Ito in the space of Disse interstitial cells of Ito in the space of Disse – Normally stores retinal- Vit A– Normally stores retinal- Vit A

Normally type I and III collagen are around Normally type I and III collagen are around the portal tract and the central veinthe portal tract and the central vein

In cirrhosis both are deposited in the In cirrhosis both are deposited in the lobuleslobules

Chronic inflammation – TNF,IL1,lyphotoxinChronic inflammation – TNF,IL1,lyphotoxin Activated Kupffer cells, endothelial cells, Activated Kupffer cells, endothelial cells,

hepatocytes, bile duct epthelial cell- hepatocytes, bile duct epthelial cell- PDGF,TGF BetaPDGF,TGF Beta

Ito cells transform to MyofibroblastsIto cells transform to Myofibroblasts 3434

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Macronodular CirrhosisMacronodular Cirrhosis

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Alcoholic CirrhosisAlcoholic Cirrhosis

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Liver Biopsy – CirrhosisLiver Biopsy – Cirrhosis

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Liver Biopsy – Cirrhosis:Liver Biopsy – Cirrhosis:

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Nutmeg Liver-Cardiac SclerosisNutmeg Liver-Cardiac Sclerosis

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Clinical featuresClinical features

Gynaecomastia –in menGynaecomastia –in men Oligomenorrhea, amenorrhea, Oligomenorrhea, amenorrhea,

sterility- in womensterility- in women

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Complications:Complications: Congestive spleenomegaly.Congestive spleenomegaly. Spontaneous bacteria peritonitisSpontaneous bacteria peritonitis Bleeding varices.Bleeding varices. Hepatocellular failure.Hepatocellular failure.

– Hepatic encephalitis / hepatic Hepatic encephalitis / hepatic coma.coma.

Hepatocellular carcinoma.Hepatocellular carcinoma.

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Alcoholic Liver Disease

Alcohol ExcessNormal

Hepatitis

Fibrosis

Cirrhosis

Steatosis

Elevated GGT

High PT and low albumin Elevated bilirubin

Elevated GGT +/- AST

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Alcoholic Hepatitis

May be initial presentation of liver disease Presents with jaundice Liver function tests mixed pattern (ALP

450 (250) + ALT 100 (50) Cirrhosis usually present (+ complications) High mortality

– 20-50%– May worsen on admission– 1-6 months resolution

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Chronic Liver DiseaseBiliary Disease

Primary biliary cirrhosis

• Background– Small bile ducts

damage

– 90% Females

• Presentation– Itching

– Abnormal liver tests

– Complications of cirrhosis (rare)

• Investigations– ALP/GGT +++

– Antimitochondrial Ab+

– Liver biopsy

• Complications– Jaundice (late)

– Progression to cirrhosis

– 10-15yrs

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Chronic Liver DiseaseBiliary disease

Primary sclerosing cholangitis

Associated Ulcerative colitisComplication Cholangiocarcinoma

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Primary Liver cell carcinomaPrimary Liver cell carcinoma Hepatocellular carcinomaHepatocellular carcinoma CholangiocarcinomaCholangiocarcinoma Hepatocellular carcinoma has a wide Hepatocellular carcinoma has a wide

variation in various parts of the world.variation in various parts of the world. Constitute 5.4% of cancers world wide.Constitute 5.4% of cancers world wide. Annual incidence range from 5- 36 per Annual incidence range from 5- 36 per

100,000100,000 Highest incidence in korea, Taiwan, Highest incidence in korea, Taiwan,

Mozambique, South eastern China.Mozambique, South eastern China. Black are attack rates 3x that of CaucasiansBlack are attack rates 3x that of Caucasians M>F ; 1.5-3: 1 M>F ; 1.5-3: 1 85% of HCC occur in countries with high rates 85% of HCC occur in countries with high rates

of HBV infectionof HBV infection 4747

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AETIOLOGYAETIOLOGY HBV- HBV chronic carrier state*HBV- HBV chronic carrier state* HCV- Anti- HCV seropositive status*HCV- Anti- HCV seropositive status* Chronic Alcoholism*Chronic Alcoholism* Food contaminants* (primarily Food contaminants* (primarily

Alflatoxin – Aspergillus Flavus in Alflatoxin – Aspergillus Flavus in grains and also Fusarium moniloforme grains and also Fusarium moniloforme in maize.in maize.

NitrosaminesNitrosamines TyrosinaemiaTyrosinaemia Hereditary haemochromatosis.Hereditary haemochromatosis. 4848

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PathogenesisPathogenesis Extensive epidemiologic studies link HBV and Extensive epidemiologic studies link HBV and

chronic HCV infection with liver cell cancer.chronic HCV infection with liver cell cancer. The development of cirrhosis is important but not The development of cirrhosis is important but not

requisite for the development of HCC.requisite for the development of HCC. Viral DNA is integrated into host genome.Viral DNA is integrated into host genome. HBV cause chronic liver damage and regenerative HBV cause chronic liver damage and regenerative

hyperplasiahyperplasia HBV expands the pool of cycling cells at risk for HBV expands the pool of cycling cells at risk for

subsequent genetic changes.subsequent genetic changes. HBV encodes a regulatory protein HBV encodes a regulatory protein HBx.HBx. HBx HBx distrupts normal growth control of infected distrupts normal growth control of infected

liver cells by activation of several growth liver cells by activation of several growth promoting genes such as Insulin- like Growth promoting genes such as Insulin- like Growth Factor I.Factor I.

HBx HBx also binds p53 and interferes with its growth also binds p53 and interferes with its growth suppressing activity.suppressing activity.

HCV- related to the chronic inflammation.HCV- related to the chronic inflammation.4949

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MORPHOLOGYMORPHOLOGY UnifocalUnifocal MultifocalMultifocal Diffusely infilterativeDiffusely infilterative FibrolamellarFibrolamellar Often background cirrhosis or chronic hepatitisOften background cirrhosis or chronic hepatitis Histology- Well differentiated to anaplasticHistology- Well differentiated to anaplastic Strong propensity for vascular invasionStrong propensity for vascular invasion HCC spread within the liver by continuous HCC spread within the liver by continuous

growth and development of satellite nodulesgrowth and development of satellite nodules Haematogenous metastasis especially to the Haematogenous metastasis especially to the

lungslungs

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DiagnosisDiagnosis

Clinical historyClinical history Biopsy/HistologyBiopsy/Histology Elevated alpha fetoprotein- in 50-Elevated alpha fetoprotein- in 50-

70% of patients with HCC70% of patients with HCC UltrasonographyUltrasonography CT, MRI, Hepatic angiographyCT, MRI, Hepatic angiography

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ComplicationsComplications

Rupture of tumour with associated Rupture of tumour with associated fatal haemorrhagefatal haemorrhage

GI/Esophageal variceal bleedingGI/Esophageal variceal bleeding Hepatic failure/comaHepatic failure/coma

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