common liver diseases

Common liver diseases+ Alcoholic liver diseases

+ Non-alcoholic fatty liver disease NAFLD

+ Autoimmune hepatitis

+ Viral hepatitis (mainly the pathology morphology will be discussed)

+ Drug-induced liver injury

+ Metabolic liver diseases (Wilson disease, Hemochromatosis, alpha-1-antitrpsin)

+ Cholestatic liver diseases (PSC, PBC, biliary atresia)

+ Neonatal giant cell hepatitis

Autoimmune hepatitis AIH

+ Immune mediated inflammatory liver disease of uncertain

cause

• More common in female patients (4-6x F > M)

• 14 - 44% have concurrent extrahepatic autoimmune

disorders, including autoimmune thyroiditis, rheumatoid

arthritis, Sjögren syndrome, vitiligo or ulcerative colitis

Autoimmune hepatitis AIHLaboratory

Serum autoantibodies:

• Antinuclear antibody (ANA): positive in 75%

• Anti smooth muscle antibody (ASMA): positive in 95%

• Anti liver kidney microsomal antibodies (Anti-LKM): associated with younger age at presentation, fulminant hepatic failure

Elevated liver enzymes; ALT / AST > ALP

Serum immunoglobulin G (IgG): marker for diagnosis (> 1.1 x upper limit of normal) and used for monitoring treatment response

Autoimmune hepatitis AIHDiagnosis

+ Diagnosis is based on combination of clinical, laboratory and histological features

• American Association for the Study of Liver Diseases (AASLD) guidance

• Elevated aspartate aminotransferase / alanine aminotransferase

• Elevated IgG or positive serological marker(s)

• Exclusion of other liver diseases resembling autoimmune hepatitis+

Autoimmune hepatitis AIHHistology

• AIH shows chronic inflammation

• Portal plasma cell rich inflammation

• With interface activity “piecemeal necrosis”

• Hepatocyte rosettes

• Variable fibrosis

• Mild lobular inflammation (portal and interface >>> lobular inflammation)

Autoimmune hepatitis AIHHistology

+ Interface hepatitis with

plasma cell rich infiltrates

Autoimmune hepatitis AIH

Histology

Hepatocyte rosette formation is one of the typical histological features of autoimmune hepatitis (AIH).

Autoimmune hepatitis AIHClinic presentation, treatment and prognosis

An acute clinical illness is a common presentation (40%); sometimes the

disease is fulminant, progressing to hepatic encephalopathy within 8

weeks of onset

Treatment: corticosteroids alone or with azathioprine

Good long-term prognosis with 10-year survival rate of 80 - 100%

Untreated AIH will lead to cirrhosis

Viral hepatitis BHBV

+ HBV causes chronic hepatitis with portal inflammation and interface activity

+ Ground glass hepatocytes (finely granular eosinophilic cytoplasm consisting of spherules and tubules of HBsAg) Arrows: ground glass hepatocytes

Viral hepatitis CHCV

• Chronic hepatitis with

predominantly

lymphocytic infiltrate,

often with lymphoid

follicles

• Lymphoid aggregates are

specific for hepatitis C but

only 50% sensitive

Portal lymphocytic infiltrates with lymphoid aggregate





+ Drug-induced liver injury (mainly the pathology morphology will be discussed)




Drug-induced liver injury

Acetaminophen- indued

liver injury:

+ Histology: extensive zone

3 or panacinar necrosis

with minimal

inflammatory infiltrates


Steatosis and steatohepatitis:

• Due to amiodarone and methotrexate


+ Bland cholestasis (anabolic steroid and OCP) as in the image

• Oral contraceptives OCP are related to hepatic lesions (focal nodular hyperplasia and hepatocellular adenoma)

Wilson disease

• Also called hepatolenticular

degeneration

• Autosomal recessive disorder

affecting 1/30,000 people

• There is accumulation of toxic

levels of copper in tissues /

organs, usually liver, brain, eye

Wilson diseasePathogenesis

• ATP7B encodes a transmembrane copper transporting ATPase located on the hepatocyte canalicular membrane, which assists with copper excretion into bile

• Wilson disease patients have genetic mutations of ATP7B that cause defective biliary excretion of copper

• Copper accumulates within the liver causing liver injury

Wilson diseaseDiagnosis

+ Serum ceruloplasmin < 20 mg/dl

+ Urinary copper excretion > 50 mcg/24 hours

+ Elevated LFT

On liver biopsies, copper can be detected using:

+ Rhodamine stain

+ Biochemical determination from liver biopsy (can use formalin fixed tissue, > 250 mcg/g dry weight)

Wilson diseaseHistologic features

Liver (pattern mimics steatohepatitis):

Fatty change with vacuolated nucleus (due to glycogen)

Acute or chronic hepatitis may be present

Cirrhosis develops late


Note the presence fat vacuoles and vacuolated nucleus (glycogenated nuclei)

Blue arrow: fat vacuolesRed arrow: glycogenated nuclei


Rhodanine stain: stains copper orange/brown color

Note the presence of copper granules in hepatocytes

Wilson diseaseTreatment

Long-term copper chelation therapy with D-penicillamine

and trientine

Zinc acetate

Liver transplantation when cirrhosis develops

Hemochromatosis

+ Autosomal recessive disorder

+ Due to mutations in iron metabolism genes such as HFE

+ Characterized by increased iron absorption, toxic iron

accumulation and end organ damage

+ Sites affected: liver, heart, pancreas, skin, gonads, joints

• M:F = 2:1, symptoms develop at 40 - 60 years old

HemochromatosisClinical features

Classic triad: 1. Liver cirrhosis2. Diabetes mellitus3. Bronzing of skin

•May also have joint pain, fatigue, abdominal pain

HemochromatosisPathogenesis

Iron is absorbed by duodenal enterocytes and transported into plasma by ferroportin

Kupffer cells take up iron and transported into plasma via ferroportin

Iron in plasma is bound to transferrin

Hepatocytes take up transferrin bound iron

Hepcidin is produced in the liver in the presence of sufficient transferrin bound iron

HemochromatosisPathogenesis

Normally Hepcidin inhibits dietary iron absorption in gut and release of iron from macrophages by inhibiting ferroportin

Hereditary hemochromatosis protein (HFE) normally promotes hepcidin transcription

Loss of function mutations in HFE → decreased hepcidin → increased ferroportin activity → increased iron absorption (Hemochromatosis)

Hemochromatosis

+ Can be primary or secondary

+ Primary: due to genetic mutations (HFE)

+ Secondary hemochromatosis (secondary iron overload), which

occurs in the setting of disorders of erythropoiesis or frequent

blood transfusions (anemia, thalassemia, repeated

transfusions)

HemochromatosisDiagnosis

• Laboratory testing

Transferrin saturation is increased

Ferritin is elevated

May have elevated liver enzymes (AST, ALT) with disease progression

Genetic testing for HFE mutations

• Liver biopsy:

o Useful to confirm diagnosis of hepatic iron overload when genetic

testing for common HFE mutations is negative

HemochromatosisGross

• Dark brown

discoloration of liver

and other involved

organs

• Hepatomegaly

HemochromatosisHistology

A. H&E: Iron appears as dark brown

granular pigment within hepatocytes

B. Prussian blue stain: stains iron blue

A B

HemochromatosisTreatment and prognosis

Prognosis:

• Good if managed before end organ damage develops

• Poor after development of cirrhosis, diabetes or cardiomyopathy

• Patients with cirrhosis have up to a 100 times greater chance of

developing hepatocellular carcinoma than the general population

Treatment: therapeutic phlebotomy and chelation therapy

Alpha-1 antitrypsin deficiency

+ Genetic metabolic disorder causing deficiency of alpha-1

antitrypsin deficiency (AAT) and leading to disease in the

lungs and liver

• Age at diagnosis: 20 - 50

• Smoking: younger age at presentation

• Infants (small subset of patients)


• AAT encoded by SERPINA1 gene - Multiple genetic variants:

• "M" = wild type allele

• "Z" and "S" = most common mutant alleles

• "Z" mutant allele accounts for 90% of disease

Normal = normal function and plasma levels of AAT

• "M" phenotype (PiMM) - Present in > 99% of world population

Deficient = abnormal function and low plasma levels of AAT

• Mutant phenotype with "Z" or "S" alleles (PiSZ, PIZZ, etc.) - < 1% of world population


• Liver complications are variable

• May be asymptomatic until adulthood

• Adults: cirrhosis, chronic hepatitis, portal hypertension,

jaundice, hepatocellular carcinoma, liver failure (rare)

• Neonates: neonatal hepatitis syndrome, cholestasis

Alpha-1 antitrypsin deficiencyDiagnosis

• Low serum concentration of AAT (< 50% of the normal reference

range = no further tests needed)

• Caution: AAT is an acute phase reactant and so may show small

elevations with systemic inflammatory states

• Absence of alpha-1 band on serum protein electrophoresis

• Genotype analysis

• Labs: elevated LFT

Alpha-1 antitrypsin deficiencyHistology

• Eosinophilic intracytoplasmic globules in hepatocytes PASD+

• Most suggestive feature of AAT deficiency

• Fibrosis: ranges from minimal to sever

• Mild portal inflammation

Alpha-1 antitrypsin deficiencyPrognosis and treatment

+ Prognosis depends on the genetic phenotype

+ Liver transplant is the only curative option

common liver diseases

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