Gi Pathology: Lecture 9 Hepatobiliary Part Ii

Front 1

INFLAMMATORY AND METABOLIC DISORDERS OF THE LIVER

Viral hepatitis

Pathology of acute viral hepatitis

T/F
Acute viral hepatitis results from an immunological response directed to viral antigens expressed in the membrane of infected hepatocytes.

Back 1

True

Front 2

INFLAMMATORY AND METABOLIC DISORDERS OF THE LIVER

Viral hepatitis

The quintessential lesion of acute hepatitis is _____________

Back 2

hepatocellular necrosis, which can take the form of apoptosis or lytic necrosis.

Front 3

Acute viral hepatitis:

Gross hallmarks:

Histological Hallmarks:

Back 3

GROSS:
- liver is heavy, diffusely red and edematous, with a tense capsule secondary to congestion and edema.

HISTOLOGICALLY:
- hepatocellular injury manifested by:
- hydropic (ballooning) degeneration,
- necrotic cells and/or apoptotic bodies,
- infiltrates of lymphocytes, and
- varying degrees of cholestasis

Front 4

INFLAMMATORY AND METABOLIC DISORDERS OF THE LIVER

Acute Viral hepatitis

Heptocellular death preferentially occurs at or near the ________ of the portal triads (i.e., interface hepatitis) resulting in ___________

Back 4

limiting plate

piecemeal necrosis

Front 5

INFLAMMATORY AND METABOLIC DISORDERS OF THE LIVER

Acute Viral hepatitis

The combination of hepatocyte necrosis and regeneration at least temporarily disrupts the orderly arrangement of plates and sinusoids, resulting in

Back 5

lobular disarray

Front 6

T/F

Like typical acute inflammation, acute viral hepatitis consists of neutrophilic infiltration and liquefactive necrosis

Back 6

False

UNlike typical acute inflammation, acute viral hepatitis LACKS neutrophilic infiltration and liquefactive necrosis.

Front 7

Chronic viral hepatitis

The most consistent histologic correlate of chronic hepatitis is

Back 7

the presence of portal mononuclear inflammatory cell infiltrates rich in CD4+ T cells.

Front 8

Chronic viral hepatitis

Common findings:

Back 8

- Varying degrees of periportal and lobular inflammation with hepatocellular necrosis

- Ongoing piecemeal necrosis results in a ragged-appearing or poorly defined portal plate

- portal and periportal fibrosis.

- bridging fibrosis

The continued loss of hepatoctyes, bridging fibrosis, and hepatocellular regeneration can progress to cirrhosis. The cirrhosis is typically macronodular or mixed micro- and macronodular with large nodules separated by broad scars.

Front 9

Chronic Viral Hepatitis

Characteristic Histological features:

Hepatitis B:

Hepatitis C

Back 9

Hep B:
- numerous “ground glass hepatocytes”

- Intranuclear inclusions containing Hepatitis B core antigen = these are known as “sanded nuclei”

HepC
- Although no histologic feature is unique to hepatitis C, the presence of

portal lymphoid follicles,

portal bile duct damage, and

lobular steatosis strongly suggest this etiology

Front 10

Chronic hepatitis is graded based on the amount of ______ and hepatocyte _______, and staged based on the ________ and _________

Back 10

graded: inflammation, necrosis

staged: distribution, extent of fibrosis

Front 11

Cytomegalovirus, Herpes Viruses, and Epstein-Barr Virus

CMV:

Back 11

- largely, but not completely, restricted to immunosuppressed patients

-can infect hepatocytes and bile duct epithelium, and the infected cells typically show cytomegaly and typical nuclear and cytoplasmic inclusions

- assoc. with non-specific microgranulomas with collections of lymphocytes and phagocytic cells or microabscesses consisting of neutrophils surrounding infected and dying cells

Front 12

Cytomegalovirus, Herpes Viruses, and Epstein-Barr Virus

HSV

Back 12

- “punched-out” coagulative hepatocellular necrosis

- with evidence of the viral inclusions around the periphery of the necrosis

Front 13

Cytomegalovirus, Herpes Viruses, and Epstein-Barr Virus

EBV

Back 13

- can occur in immunocompetent hosts (“mononucleosis” is usually due to EBV) or in immunocompromised hosts.

- In the former, the histologic feature is “beads on a string” due to the atypical lymphocytes traveling through the sinusoids.

- Very little hepatocyte injury is noted.

Front 14

Bacterial, Fungal, and Mycobacterial Infections

Bacterial infections usually occur in one of two settings:

Back 14

1) bacterial sepsis - usually characterized by canalicular cholestasis, periportal Canal of Hering bile stasis (cholangitis lenta) and lobular infiltrates of neutrophils, except with profound leukopenia.

2) ascending biliary infection - usually characterized by neutrophils within and surrounding portal bile ducts.

Front 15

Bacterial, Fungal, and Mycobacterial Infections

Fungal infections predominantly occur in the setting of

Back 15

fungemia, most often in immunosuppressed patients.

As in other tissue sites, the tissue reaction can vary from neutrophilic to granulomatous inflammation, depending on the organism and immunocompetence of the host.

Front 16

Bacterial, Fungal, and Mycobacterial Infections

Tuberculous

Back 16

- follows miliary dissemination and is typically associated with caseating granulomas

- old fibrotic granulomas usually indicate prior infection.

Front 17

Liver Abscess

Most abscesses are caused by _________; which can reach the liver through the _______, ________, or in an ascending manner through the __________ .

Back 17

bacteria

portal vein, hepatic artery or in an ascending manner through the biliary tract (acute ascending cholangitis)

Front 18

Liver Abscess

T/F

The bacteria most commonly implicated in abscesses are E. coli and other coliforms.

Back 18

True

Front 19

Liver Abscess

Typical clinical features of liver abscess:

Back 19

Fever,
Leukocytosis,
Upper abdominal pain,
Solitary or multiple hepatic nodules

(regardless of etiology)

Front 20

Liver Abscess

Two of the most important parasitic infections are:

Back 20

amoebiasis and hydatidosis

Front 21

Liver Abscess

Parasitc Infections

Amoebiasis:

Back 21

- caused by Entamoeba histolytica

- organisms reach the liver via the portal venous system, after invasion in the large intestine

- right lobe of the liver receives most of the portal venous flow and most frequently affected by amebic abscesses.

- usually multiple, 5 to 20 cm in diameter, and lack a fibrous capsule

- contents consist of a red-brown paste like material

- Trophozoites can be recognized on microscopic examination

- Complications include pleural and pulmonary fistulas (through the diaphragm) and the often lethal rupture into the peritoneal cavity with the ensuing amebic peritonitis.

Front 22

Liver Abscess

Parasitc Infections

Hydatidosis is caused by:

Back 22

- caused by equinococcus granulosus

- eggs of E. granulosus hatch in the GI tract and the larval oncospheres gain access to the portal vein through the intestinal circulation

- the cysts grow slowly in the liver and can reach up to 30 cm in diameter, but are usually asymptomatic

- the cyst is surrounded by a fibrous rim and can be unilocular or contain daughter cysts

- uncomplicated cysts can become secondarily infected

- they can also rupture and elicit an anaphylactic reaction and/or seed the abdominal cavity.

Front 23

AUTOIMMUNE HEPATITIS

T/F

Autoimmune hepatitis occurs concomitantly with lupus

Back 23

False

Autoimmune hepatitis does NOT occur concomitantly with lupus even though they both can have positive ANA.

Front 24

AUTOIMMUNE HEPATITIS

Clinical presentation:

Diagnosis:

Back 24

- The clinical presentation and sometimes the pathology can be indistinguishable from viral hepatitis

- the diagnosis depends on absence of evidence of viral infection; typically, total plasma proteins are elevated due to globulins, particularly elevated IgG.

- the diagnosis can be challenging and can sometimes require evidence of response to therapy

- the disease is often responsive to immunosuppressive therapy, and typically requires lifetime immunosuppression

Front 25

AUTOIMMUNE HEPATITIS

2 types of autoimmune hepatitis:

Back 25

Type 1
- About 70% female, and most are under 40 years of age.

- Characteristic serologic findings include:
hypergammaglobulinemia,(predominantly IgG) and variably the presence of anti-smooth muscle (SMA) and anti-nuclear (ANA) antibodies.

- Associated diseases include autoimmune thyroiditis, Grave’s disease, and ulcerative colitis.

Type 2
- Predominantly affects children.

- It is serologically typified by antibody reactive with liver/kidney microsome type 1 (anti-LKM1).

- Patients can have associated immunologic disorders such as:
vitiligo, thyroiditis, insulin dependent diabetes, autoimmune and pernicious anemia, rheumatoid arthritis and ulcerative colitis

Front 26

AUTOIMMUNE HEPATITIS

Histologically, autoimmune hepatitis is characterized by:

Back 26

- marked interface hepatitis
- often with abundance of plasma cells
- hepatitic rosettes
- Lobular (acinar) inflammation,
- bridging necrosis
- disease can present as chronic, acute or fulminant hepatitis, or cryptogenic cirrhosis

Front 27

DRUG INDUCED LIVER DISEASE

Drug-induced liver disease increases with ___

Back 27

age.

Front 28

DRUG INDUCED LIVER DISEASE

Direct (predictable, intrinsic) toxicity occurs with:

Back 28

- occurs with drugs or chemical compounds known to produce liver damage in a dose dependent manner

- the acute pattern of injury is exemplified by focal or massive hepatocyte necrosis, cholestasis or combinations of both

- chronic injury can present in the form chronic hepatitis (morphologically indistinguishable from viral hepatitis and other hepatitides), granulomatous inflammation, microvesicular and macrovesicular fatty change, parenchymal fibrosis, vascular changes in the form of peliosis, or neoplasia.

Front 29

DRUG INDUCED LIVER DISEASE

Indirect (unpredictable, idiosyncratic) toxicity is:

Back 29

the consequence an immune-mediated reaction in which the drug acts as an antigen or a hapten

- It can also result when a drug slows the metabolism of the drug or one or more of its byproducts, which in itself is a hepatic toxin if not quickly or properly disposed of.

Front 30

ALCOHOLIC LIVER DISEASE

Alcohol produces an imbalance of several metabolic pathways that can culminate in:

Back 30

alcoholic steatosis,
alcoholic hepatitis,
alcoholic cirrhosis

Front 31

ALCOHOLIC LIVER DISEASE

Alcoholic steatosis / alcoholic fatty liver

Back 31

- Moderate alcohol intake induces the formation of small, membrane-bound cytoplasmic fat vacuoles (small droplet steatosis) secondary in part to increased lipid biosynthesis and impaired assembly and secretion of lipoproteins.

- with continuous ingestion (chronic alcoholism) the vacuoles merge and form large cytoplasmic vacuoles (macrovesicular or large droplet steatosis).

- Although steatosis begins around the central vein (zone 3), it can involve the entire hepatic lobule.

- In severe cases, the liver appears enlarged and yellow.

- Perivenular and perisinusoidal (“chickenwire”) fibrosis is believed to precede the development of cirrhosis

- Clinically, steatosis can be asymptomatic, manifest itself as mild hepatomegaly, or produce mild elevations of bilirubin or alkaline phosphatase.

Front 32

ALCOHOLIC LIVER DISEASE

Alcoholic hepatitis

Back 32

- acute presentation

- manifestations range from mild to acute fulminant hepatic failure

- Malaise, anorexia, tender hepatomegaly and leukocytosis are common findings.

- hyperbilirubinemia and elevation of alkaline phosphatase and other liver enzymes are found.

- histologic hallmarks of alcoholic hepatitis are hepatocyte swelling (ballooning) and necrosis, the presence Mallory-Denk bodies (cytoplasmic accumulations of tangled skeins of cytokeratins 8/18) and neutrophilic infiltration of the hepatic lobule, commonly around hepatocytes containing Mallory-Denk bodies (“satellitosis”).

- Mallory-Denk bodies can also be seen in cholestatic liver diseases (PBC, PSC), as well as in Wilson's disease, and hepatocellular tumors.

- Fibrosis initially in a perisinusoidal distribution in zone 3 and around central veins; however, portal and periportal scarring also occurs

Front 33

ALCOHOLIC LIVER DISEASE

Alcoholic Cirrhosis

Back 33

- the most serious manifestation of ethanol toxicity is alcoholic cirrhosis, which occurs in 10 to 15 % of alcoholics

- Women more susceptible to this complication.

- Alcohol is the most common cause of cirrhosis and is a common promoter of fibrosis with HCV infection.

- liver grossly varies from enlarged and yellow (due to steatosis) to shrunken and brown (due to associated iron deposition).

- Pattern of cirrhosis may be micro or macronodular.

- Presentation ranges from asymptomatic to full blown chronic hepatic failure with manifestations of severe portal hypertension.

Front 34

T/F

Steatosis is a reversible change if cessation of alcohol consumption occurs.

Back 34

True

Front 35

NON-ALCOHOLIC FATTY LIVER DISEASE

Etiologically attributed to:

Presentation:

Back 35

- etiologically attributed to insulin resistance and is considered as the hepatic manifestation of the Metabolic Syndrome, a constellation of central obesity, glucose intolerance, hypertension and hyperlipidemia

- presents as a spectrum from steatosis, to nonalcoholic steatohepatitis (NASH), to cirrhosis.

Front 36

INHERITED METABOLIC DISORDERS ASSOCIATED WITH HEPATOCELLULAR INJURY

Name 3

Back 36

Hemochromatosis - excessive iron accumulation in hepatocytes

Wilson disease - excessive copper accumulation

alpha 1- antitrypsin (AAT) deficiency

Front 37

INHERITED METABOLIC DISORDERS ASSOCIATED WITH HEPATOCELLULAR INJURY

All discussed here share the following characteristics:

Back 37

- Autosomal recessive inheritance and cause disease in homozygotes

- Although all can present in childhood, liver disease can stabilize or regress prior to further progression in adult life, or initially present in adults

- all can progress to micronodular or mixed cirrhosis

- initially involve periportal hepatocytes but can progress to diffuse lobular involvement

Front 38

INHERITED METABOLIC DISORDERS ASSOCIATED WITH HEPATOCELLULAR INJURY

Hemochromatosis

Back 38

defined as the excessive accumulation of body iron, with deposits in organs such as the liver and pancreas in the context of associated liver disease

Front 39

Abnormal iron accumulation without associated injury, whether hepatocellular or reticulo-endothelial, is referred to as

Back 39

hemosiderosis

Front 40

Clinical manifestations of extrahepatic organ involvement in hemochromatosis include:

Back 40

Diabetes,

Cardiac dysfunction,

Skin pigmentation (due to increased melanin) and

Arthritis

Front 41

Hemochromatosis

Characterize the most common hereditary form of the disease:

Back 41

- C282Y homozygous HH, or type 1 caused by point mutations in the gene encoding HFE, a membrane protein that regulates hepatocellular expression of hepcidin

- Downstream effects include increased iron absorption in intestinal epithelial cells as well as increased macrophage release of iron stores

- mutant HFE is defective in sensing cytoplasmic iron levels, leading to unregulated expression of metal transporter proteins in intestinal cells

- In the absence of a regulatory mechanism, there is a progressive accumulation of iron, which eventually causes organ damage and symptoms

Front 42

There are 4 types of hereditary hemochromatosis. All are related to the effect of the mutation with the:

Back 42

“master iron regulator”, hepcidin

Front 43

In the liver, hemosiderin and ferritin initially accumulates in the _________.

However, as the diseases progress the entire lobule is affected.

Iron is directly hepatotoxic, leading to _________ and _________. With late disease, the liver is______, _________, and _________.

Back 43

initially accumulates in the:
- periportal hepatocytes

leading to:
- fibrosis and micronodular cirrhosis

late disease, liver is:
- reduced in size, appears nodular and has an intense red-brown color

Front 44

T/F

Hemosiderin accumulation is also seen in the myocardium, and joint synovial lining.

Back 44

True

Front 45

Hemochromatosis

Diagnosis:

Treatment:

Causes of death include:

Back 45

Determination of hepatic iron levels has traditionally been used to establish the diagnosis.

The initial treatment involves regular phlebotomy to deplete body iron.

Causes of death include cardiac disease, cirrhosis, and hepatocellular carcinoma.

Front 46

T/F

Hemochromatosis is associated with an approximate 200-fold increase in the risk of liver cancer.

Back 46

True

However, the development of cancer does not require prior cirrhosis.

Front 47

Wilson disease

Characteristic features:

Back 47

- excessive copper accumulation

- accumulation of copper in the liver, brain and eyes, and other organs.

- copper absorbed in the intestine is transported to the liver where it is taken up by hepatocytes and coupled with an a-globulin to form ceruloplasmin.

- as the protein ages, it is recaptured by the hepatocytes, degraded, and the copper is excreted into the bile, thus constituting the main route for copper excretion

Front 48

Wilson disease

Pathogenesis:

Back 48

Mutations in the Wilson disease gene (ATP7B) result in an abnormal transmembrane copper transporting ATPase with defective biliary copper excretion.

As a result, copper accumulates in the liver with resulting hepatic damage and elevated blood copper levels, which lead to toxicity in the basal ganglia of the brain and many other organs.

The disease rarely becomes evident before six years of age.

Front 49

Wilson's Disease:

Classical Clinical Sign:

Most common clinical manifestation:

Back 49

Copper deposition in the cornea causes a classical clinical sign, the green-brown Kayser-Fleischer ring

Acute or chronic hepatitis is the most common initial clinical manifestation.

Front 50

Alpha 1- antitrypsin (AAT) deficiency

Back 50

- alpha 1- antitrypsin (alpha 1- antiprotease) is a protease inhibitor that neutralizes the actions of the neutrophil serine proteases: elastase, cathepsin G and proteinase 3.

- A specific substitution in the Z allele causes defective folding and secretion from ER with subsequent accumulation of the misfolded protein in the cytoplasm of the periportal hepatocytes.

- This seems to initiate cell stress and an autophagocytic process, which contributes to the hepatic damage

-A1AT-related cirrhosis may develop HCC

Front 51

Alpha 1- antitrypsin deficiency is recognized in liver biopsies by the:

Back 51

- Presence of eosinophilic globular hepatocellular inclusions consisting of the retained, misfolded protein

- The changes preferentially occur in the periportal hepatocytes for reasons that are unclear.

- The inclusions stain for PAS following diastase treatment, but can be more specifically identified using immunoperoxidase assays for alpha 1- antitrypsin.