Pathology Lecture 7 Liver pathology

CCL07 Conditions of the liver

1. Alcoholic liver disease
Pathological changes to the liver occur progressively through the spectrum of ALD

Alcoholic fatty liver disease

Soft, pale yellow liver
Spongy appearance due to fat-filled vacuoles
Hepatomegaly

Alcoholic steatohepatitis
Hepatocyte necrosis with focal reticulin collapse
Mallorys hyaline bodies (intracellular eosinophilic i.e. red aggregates of cytokeratines)
Focal neutrophil infiltrate

Alcoholic fibrosis
Chicken-wire fibrosis (network of intra-lobular connective tissue surrounding cells & venules)
Result of cytokines/chemokines from Kuppfer cells stimulating collagen production via hepatic stellate
cells

Alcoholic cirrhosis
Attempted hepatocyte regeneration
Formation of non-functioning regenerative micronodules
Interrupted bile flow
Deranged blood flow with abnormal anastomoses
Portal hypertension
 Causes of hepatic decompensation mnemonic: HEPATICUS

Haemorrhage/hypoglycaemia/HCC

Electrolyte imbalance

Protein load/Paracetamol OD

Alcohol

Trauma

Infection/ischaemia (portal vein thrombosis; Budd-Chiari syndrome)

Constipation

Uraemia

Sedatives/shunts/surgery

Complications of decompensation
Hepatic encephalopathy
o Drowsy coma
o Confusion
o Constructional apraxia
Portal hypertension
o Ascites
o Bleeding (haemorrhage, haemorrhoids)
o Caput medusae
o Diminished liver
o Enlarged spleen
Hyperoestrogenaemia
 Portal hypertension complications
1. Enlargement of collateral veins
- Gastro-oesophageal junction with varices & haematemesis
- Periumbilical region with prominent subcutaneous veins (caput medusa)
- Splanchnic vascular congestion with ascites
2. Splenomegaly +/- hypersplenism
o Hypersplenism = rate of RBC, leukocyte +/- platelet destruction

3. Non-alcoholic fatty liver disease (NAFLD)

Primary NAFLD
Identical histological findings to ALD (inc Mallory hyaline bodies), but not associated with alcohol use.
More associated with micro-vesicular steatosis & nuclear vacuolisation
Considered part of metabolic (insulin resistance) syndrome

Metabolic syndrome diagnostic criteria

- Central obesity
- Impaired glucose tolerance (T2DM)
- Dyslipidaemia
- Hypertension

Metabolic syndrome NAFLD NASH Cryptogenic cirrhosis (with no steatosis)

Secondary NAFLD
- Drugs e.g. amiodarone, steroids, tamoxifen
- Surgical procedures e.g. extensive bowel resection, gastroplasty
- TPN
4. Acute hepatitis
Acute-onset inflammation of hepatocytes with associated necrosis.

Causes
1. Infectious agents e.g. HAV, HBV, HCV, delta HV
2. Autoimmune hepatitis due to T-cell mediated autoimmunity
3. Drug-induced due to direct drug-toxicity, immune-mediated injury
4. Idiopathic

Clinical sequence
i. Pre-icteric phase
- Fever, nausea, vomiting, epigastric pain, myalgia, hepatic tenderness

ii. Icteric phase

a. Jaundice, dark urine + pale stools, peripheral blood lymphocytosis

Outcomes
Complete recovery
Chronic hepatitis
Cirrhosis
Massive liver necrosis +/- HCC

Hep A

Acute, benign & self-limiting

Hep B

Can lead to rapid death due to fulminant/massive liver cell necrosis

Generally chronic, associated with cirrhosis, HCC
Endemic in SE Asia
Presence of lymphocytes
Ground glass-like cytoplasm
 Hep C

Less likely to cause death short-term; more associated with chronic deaths
High incidence of progression to chronic hepatitis (80%)
Associated with carrier status & drug abuse

Hep D

Incomplete virus requires Hep B surface antigens for proliferation

Always occurs in tandem with Hep B

Autoimmune hepatitis

Most common demographic young women

Classified under type I, IIa, IIB and III according to presence/absence of specific autoantibodies
Large numbers of lymphocytes present T-cell mediated autoimmune reaction
o Focal lymphocytic infiltrate
o Absence of neutrophils/macrophages
NB: anti-smooth muscle antibody + antinuclear antibody = hallmark diagnostic

Sequence from hepatitis to cirrhosis

5. Cirrhosis
Liver damage characterised by diffuse distortion of hepatocyte architecture, bridging fibrosis (subdividing
parenchyma) and regenerative nodules.

Clinical features of cirrhosis Mnemonic: ABCDEFGHI PS

Asterixis/ascites

Bruit/bruising (purpura, epistaxis)

Cachexia/Caput medusa

Dermatogenic symptoms

Edema/encephalopathy

Fetor hepaticus

Gynaecomastia/testicular atrophy/impotence/irregular menses/amenorhoea

Hepato-renal/-pulmonary syndrome/hepatomegaly

Icterus

Palmar erythema/portal hypertension

Spider naevi

Types of cirrhosis
i. Macronodular (nodules >3mm diameter)
- Chronic active viral hepatitis B&C
- Drugs

ii. Micronodular (nodules <3mm diameter)

- Chronic alcoholism

Causes of cirrhosis Mnemonic: HEPATIC Complications of cirrhosis Mnemonic: VARICES

Haemochromatosis Varices

Enzyme deficiency (-1 antitrypsin) Anaemia

PBC/Post-hepatic (infection/drug-induced) Renal failure

Alcohol Infection

Tyrosinosis Coagulopathy

Indian childhood (galactosemia) Encephalopathy

Cardiac/cholestatic (biliary)/cancer/copper (Wilsons) Sepsis

 Haemochromatosis
Genetic disease due to abnormal accumulation of iron in the liver may lead to HCC

How to distinguish b/w haemochromatosis and chronic haemolysis

Peripheral blood smear

Reticulocyte count
Serum LDH
Liver biopsy

Complications of haemochromatosis Mnemonic: HaemoChromatosis Can Cause Deposits Anywhere

Hypopituitarism/hypogonadism

Cancer (HCC)/colouring (skin pigmentation)

Cirrhosis

Cardiomyopathy/cardiac failure

Diabetes

Arthropathy
 -1 antitrypsin deficiency
Caused by the absence of inactivation protein for -1 antitrypsin. Patients develop:

Panlobular emphysema
Chronic hepatitis
Micronodular cirrhosis
Abnormal accumulation of -1 antitrypsin in hepatocytes
NB: PAS stain used for diagnosis

Primary Biliary Cirrhosis (PBC)

Affects middle aged elderly women (90%)
Characterised by chronic autoimmune destruction of intrahepatic bile ducts
Patients present with:
o Pruritis
o Skin hyperpigmentation
o Xanthoma
o Xanthelesma (inappropriate lipid breakdown)
Diagnosed using anti-mitochondrial antibody (detectable in ~90% of affected patients)

NB: Often associated with concurrent non-organ specific AI diseases e.g. autoimmune thyroiditis

6. Cholestasis (bile stasis)

Obstruction within the biliary tract which prevents entry of bile into the duodenum. There are 2 types:

i. Intrahepatic/hepatocellular cholestasis
Cholestatic drugs Mnemonic: CHOLESTATIC

Chlorpromazine/contraceptive (OCP)
Ofloxacin
Largactil (i.e. chlorpromazine)
Erythromycin/Gentamicin
Sulfamethoxazole
Trimethroprim
Augmentin
Tetracycline
Ibuprofen
Cimetidine

ii. Extrahepatic
cholestasis/obstructive jaundice

Dark brown mucous plugging in dilated biliary tree

7. Hepatic granulomas
Granuloma = organised compact <2mm ball-like clusters of cells caused by prolonged inflammatory response to
foreign organism/antigen in the liver.

Histological features:

Epithelioid macrophages w elongated & enlarged nuclei (slipper/shoe-like

nuclei)
Pink, more eosinophilic cytoplasm
Poorly defined individual cell-borders
Can have lymphocytes/neutrophils/eosinophils/multinucleated giant
cells/fibroblasts/collagen

Causes of granulomas

8. Hepatic neoplasm
Benign

Hepatocellular adenoma (tumour of hepatocytes)

Cavernous haemangioma (tumour of blood vessels)

Malignant

Hepatocellular carcinoma (HCC) (malignancy of hepatocytes)

Cholangiocarcinoma (malignancy of bile duct epithelium)
Metastatic carcinoma e.g. from GIT, lung, breast, leukaemia

Hepatocellular carcinoma
Most common kind of hepatic malignancy
Can present as solitary intrahepatic mass or multiple masses (metastasis)
Primary HCC tumours are generally well-defined and arises in setting of cirrhosis
Will show mosaic arrangement of atypical hepatocyte-like cells
Cholangiocarcinoma
Most common in pt between 50 70y.o.
Carcinoma of biliary duct epithelium with white scar-like appearance
Have prominent fibrosis surrounding carcinoma cells
Histology
o Glandular tumour cells
o NB: histological features may be identical to gallbladder or pancreatic cancer

Hepatic metastases
Common in patients with disseminated carcinoma or arising in areas drained by the portal venous system
Metastases tend to have multinodular, well-defined appearance
Can have umbilication i.e. central depression in liver due to necrosis/fibrosis
From the TORG
LO1 Recognise the role of liver biopsy in persistently abnormal LFTs

LO2 Discuss normal fat metabolism by the liver and list the causes of fatty liver
Causes of fatty liver

Alcohol
Erythromycin + pregnancy (acute fatty liver of pregnancy)

LO3 Interpret Fe2+ studies

LO4 Recognise Fe2+ overload in the liver

See matrix on Haemochromatosis

LO5 Active and chronic hepatitis

LO6 Clinical symptoms, signs and causes of cirrhosis