patho sheet # 3 - Huda 3awamleh

Hello,, my sheet is copy paste from the doc slide so there is no need to read them I will write the extra explanation btw ( ) and there is a subject which is primary biliary cirrhosis I didn’t find it in the slide so u must read it from this sheet ;]

We start our lec by mention the clinical features of hemochromatosis ; male predominate[5-7:1]with slightly earlier clinical presentation partly bcz of physiologic iron loss, in women ( menstruation&pregnancy ). In the most common form caused by HFE mutation symptom appear in the 5th to 6th decades of life .the principle manifestation include : hepatomegaly ,abdominal pain ,skin pigmentation [particularly in sun exposed areas] ,diabetis mellitus ,cardiac dysfunction and atypical arthritis.
In some individuals the presenting symptom are amenorrhea in females and loss of libido and impotence in males ( bcz the pituitary can be affected by iron accumulation).
Death may result from cirrhosis ,hepatocellular carcinoma or cardic disease.
Treatment of iron overload doesn’t remove the risk for development of hepatocellular carcinoma ,bcz of the oxidative damage of DNA produced by iron .
The natural course of the disease can be altered by a variety of interventions ,mainly phlebotomy ( taking blood from vein )and the use of iron chelator to drain off excess iron .
Patient diagnosed in the precirrhotic stage and treated by regular phlebotomy have a normal life expectancy.
Heterozygotes may show a mild increase in iron absorption and accumulation.
Refer to the book fig 16-21 (its section in the liver ,large amount of iron in hepatocyte due to accumulation of iron in hemochromatosis ,in normal individual we can see small amount of iron but not as much as the figure )


Wilson disease
An autosomal recessive disorder of copper metabolism charactarizedby the accumulation of toxic levels of copper in many tissues and organ ,principally the liver ,the brain and the eye .
The genetic defect responsible for Wilson disease is a mutation in ATP7B. located on chromosome 13 and encodes an ATPase metal ion transporter that localize to the golgi region of hepatocytes .
90-95% of plasma copper is bound to ceruloplasmin and the liver takes up desialylated senescent ceruloplasmin from plasma then its degraded and free copper is secreted free into bile.
In wilson disease copper absorption and transport to the liver is normal but absorbed copper fails to enter the circulation in the form of ceruloplasmin and biliary secretion of copper is markedly decreased.
Defective function of ATP7B leads to excrete copper into bile ,the primary of copper excretion from the body .
The biochemical diagnosis of Wilson disease is based on a decreased serum ceruloplasmin ,increased hepatic copper content and increased urinary excretion of copper .( Q: how we measure the hepatic copper content ? A: we take a dry weight liver tissue and we measure the copper content .)
In the liver it can result in fatty change ,acute hepatitis, chronic hepatitis with progression to cirrhosis .
In the brain ,toxic injury primarily affects the basal ganglia , particularly the putamen.
Nearly all the patient with neurologic involvement develop eye lesion called kayser-fleischer(when there is a rings in the periphery on iris their color golden to brown or golden to green).


Clinical feature :
Rarely present before 6 years of age .the most common manifestation is acute or chronic liver disease . neuropsychiatric disorder are initial feature in most often cases.
Demonstration of kayser-fleischer rings or markedly elevated hepatic copper levels in a persomn with a low serum ceruloplasmin value strongly favor the diagnosis of Wilson disease.
Early diagnosis and long term copper chelation therapy [as with d-penicillamine ]have dramatically altered the usual progressive downhill course .

Another metabolic disorder we r going to talk about the unknown alpha1-antitrypsin deficiency:
AATdeficiency is an autosomal recessive disorder marked by abnormally low serum level of this protease inhibitor, the major function of AAT is the inhibition of neutrophil elastase at the site of inflammation (just neutrophil elastase ).
AAT deficiency resulting emphysema due to unrestrained activity of tissues destructive proteases.
AAT is a plasma glycoprotein synthesized primarily in the liver , the AAT gene is present on chromosome 14, is very polymorphic ,and at least 75 form have been identified.
Homozygotes for the z alleles have circulating AAT levels 10%of normal and heterozygotes have intermediate level.
Bcz the mutant prtn cannot be secreted from hepatocyte ,it accumulate in the endoplasmic reticulum of the hepatcyte.
Although all individuals with AAT deficiency contain round to oval cytoplasm globular inclusion which are strongly PAS (periodic acid schiff ) positive. Injury to heptocyte may range from colestasis with necrosis in new born to childhood cirrhosis or to asmoldering chronic inflammatory hepatitis or cirrhosis that become apparent only late in life.
Clinical course :among newborn with AAT deficiency 10-20% show cholestasis ,in older children , adolescent and adults ,presenting symptoms maybe related to chronic hepatitis , cirrhosis or pulmonary disease . ( as we said it cause emphysema in the lung .why ?bcz it destruct the elastic tissue in cepte of alveoli so it cause emphysema ).
The disease may remain silent until cirrhosis appears in middle to later life .hepatocellular carcinoma develop in 2-3% of piZZadult ,usually but not always in the setting of cirrhosis.
The treatment and cure for severe liver disease is liver transplantation .

Neonatal cholestasis:
Prolonged conjugated hyperbilirubinemia in the newborn , termed neonatal cholestasis ,affect 1in 2500 live births.
The major causes are extrahepatic biliary atresia and a variety of other disorders collectively known as neonatal hepatitis , idiopathic neonatal hepatitis constitute as many as 50% of cases of neonatal hepatits .
Infants present with jaundice ,dark urine ,light acholic stool, and hepatomegaly .
Differentiation between the two most common causes of neonatal cholestasis [biliary atresia ad idiopathic neonatal hepatitis ]assumes great importance, bcz definitive treatment of biliary atresia requires surgical intervention ,whereas surgery may adverse affect the clinical course of child with idiopathic neonatal hepatitis ,this can be doe in 90%of cases by liver biopsy .

Reye syndrome:
Is a rare disease characterized by fatty change in the liver and encephalopathy .the more severe forms are fatal .
It primarily affects children younger than 4 years of age ,typically developing 3 to 5 days after a viral illness .
The onset is heralded by pernicious vomiting and is accompanied by irritability ,lethargy and hepatomegaly.
Serum bilirubin ,ammonia and aminotransferase and particularly ammonia.
Death occurs from progressive neurologic deterioration or liver failure survivors may be left with severe neurologic impairment .
The pathogenesis of reye syndrome involve generalized loss of mitochondrial function ,reye syndrome is now recognized as the prototype of a wide variety of conditions known as mitochondrial hepatopathies ..reye syndrome has been associated with the administration aspirin during viral illnesses ,but there is no evidence that salicylates play a causal role .
Morphologically in the liver it cause microvesicular fatty change and pleomorphic large mitochondria seen in E.M (electron microscope) .
In he brain it causes cerebral edema but inflammation is notably absent .
Skeletal muscle ,kidneys and heart may also show microvesicular fatty change and mitochondrial alterations.


Primary biliary cirrhosis:
Is a chronic ,progressive and often fatal cholestatic liver disease , characterized by the destruction of intrahepatic bile ducts ,portal inflammation and scarring and the eventual development of cirrhosis and liver failure over years to decades .
The primary feature of this disease is a nonsuppurative destruction of small and medium –sized intrahepatic bile ducts ; cirrhosis appears only late in the course . in the early lesions there is a dense lymphocyt /plasma cell infiltrate around small also appear.primary biliary cirrhosis is primarily a disease of middle aged women, with an age at onset between 20&80 years and peak incidence between 40&50years of age .
Pathogenesis and clinical course .more than 90%of persons with primary biliary cirrhosis have high titers ofantimitochondrial antibodies.theseantibodiesare directed to specific domains of mitochondrial acid dehydrogenase enzymes.
The onset of primary biliary cirrhosis is insidious, usually presenting as pruritus; jaundice develops late.
Serum alkaline phosphatase and cholesterol levels are almost always elevated ;hyperbilirubinemia is a late development and usually signifies incipient hepatic failure ,associated extrahepatic conditions include the sicca complex of dry eyes and mouth [sjogren syndrome] ,scleroderma, thyroiditis ,rheumatoid arthritis ,raynaud phenomenon ,membranous glomerulonephritis and celiac disease .
Refer to fig.16-23 ( it’s a section through the liver , note the greenish discoloration of the primary biliary cirrhosis ).
Fig.16-24(granuloma formation around small biliary ductile. ).

Primary sclerosing cholangitis:
Is a chronic cholestaticdisease ,characterized by progressive fibrosisofextrahepatic and large intrahepatic bile ducts.
Bcz the changes are patchy , retrograde chalangiography
(they make endoscopy through the GIT to enter biliary tract and inject a contrast medium in biliary tree in the 2nd part of duodenum abulla of vator , through the abulla of vator we enter the pancreatic and biliary tree ,, in the biliary tree we inject the contrast medium it will go to the biliary tree ,either on gallbladder or liver so 2za sawarnaha we will see the biliary tree and gallbladder ,so if we make cholengography with contrast medium in primary sclerosing cholangitis we will see the intrahepatic bile duct and extrahepatic bile duct ,they give as beading cz they contain fibrosis which is not continuous segment constructed and segment dilated we call it beading .).
Shows a characteristic [beading] of the contrast medium in the affected segments of the biliary tree.
The large bile duct show periductal fibrosis that obliterate the lumen ,leaving a solid cord scar with few inflammatory cells .
Primary sclerosing cholangitis is commonly seen in association with inflammatory bowel disease ,particularly ulcerations colitis ,which coexist in 70% of cases , conversely the prevalence of primary sclerosing cholangitis in patients with ulceration colitis is about 4%.
The disorder tend to occur in the 3rd through the 5th decade often after the development of inflammatory bowel disease.
Males are affected more common than female [2:1].
The course of primary sclerosing cholangitis is unknown ;the association with ulceration colitis ,the linkage with certain HLA-DR alleles ,and the presence of antinuclear cytoplasmic antibodies (ANCA) with perinuclear localization (PANCA)in 80% of cases all suggest that it is an immunologically mediated disease .
Symptom at presentation include progressive fatigue ,pruritus and jaundice . asymptomatic patients may come to attention only on the basis of persistant elevation of serum alkaline phosphatase.(cz it involve the biliary tract and biliary epithelium so destruction of biliary epithelium gives alkaline phosphatase enzyme its an isoenzyme similar to osteoblast.)primarysclerosing cholangitis generally has a protracted courseover many years ,cholangiocarcinoma may develop in 10%to15%of individuals with a median time of 5 years from diagnosis.
There is no effective therapy and the disease has become an important indication for liver transplantation .


liver tumors

hepatocellular nodules

- focal nodular hyperplasia
a localized , well demarcated but poorly encapsulated lesion , consisting if hyperplastic hepotocytes with central fibrous scar .

it is not a neoplasm but occurs in response to local vascular injury.
It is usually an incidental finding , most commonty in women in reproductive age , and does not carry a risk for malignancy .
20% of cases coexist with hepatic cavernous hemangioma .
- Macroregenerativenodules : appear in cirrhotic livers , they are larger than surrounding cirrotic nodules but do not display atypical features . they do not carry risk for malignancy

- dysplastic nodules :- are larger than 1 mm that appear in cirrhotic livers with hyperproliferative hepatocytes showing atypical features such as pleomorphism and crowding .

the dysplastic features can be if low or high grade . high grade lesions are considered to be precursors if hepatocellular cancers . dysplastic lesions are divided into small cell and large cell dysplastic nodules .only small cell dysplasias are precursers for canacers .
Benign tumors



Cavernous hemangioma:

The most common benign tumor of the liver is cavernous hemangioma .they appear as discrete red blue lesions , usually less than 2cm in diameter , after directly beneath the capsule . blind percutaneous need be biopsy may cause severe intra abdominal bleeding.
Hepatic adenoma:
usually occurs in women of child bearing age who have used OCPs( oral contraceptive pills) and it may regress on discontinuance of the hormone .

these are well demarcated lesions , often beneath the capsule may be yellow tan or bile stained .
they are composed of sheets and cords of cells that may resemble normal hepatocyte or have some variation in cell and nuclear size .

liver adenomas significant for :

-they can be mistaken for cancer(bcz they r mass lesion in liver)
- they can rupture during pregnancy (and cause bleeding czbseer 2lhom hormone stimulation cz the estrogen bertafe3 during pregnancy and they r estrogen dependent hormone so they will increase in size and repture and czintra abdominal hemorrhage)
- adenoma with b-catenin mutatiors carry a risk of developing into cancer.


Hepatocellular carcinoma( HCC):
Constitute 5.4% if all cancers
- 85% occur in areas of chronic HBV(hepatitis b virus) infection [vertical transmission ]
Aflatoxin exposure when combined with HBV infection increases the risk .[ 200fold ]
Peak incidence between 20-40 years of age, 50% appear in the absence cirrhosis
- in western population present before age 60 and 90 % of cases in persons with cirrhosis .
These major etiologic associations
HBVorHCV
Alcoholism
Aflatoxin[ derived from aspergellusFlerius]
The development of cirrhosis seems to be an important but not requisite contributor.
With HCV HCC occurs only in the presence of cirrhosis (it not true about HBV or other precursors)an almost universal feature of HCC is the presence of chromosomal abnormalities both structural and numeric.
Neither HBV nor HCV contain oncogenes the tumorigenic capacity of these viruses probably relates primarily to their capacity to cause continuous cell death , chronic inflammation and regeneration (stimulation of repair and inflammation and regeneration they think all of this will lead to cancer development) .



Clinical features :
Although primary carcinomas in the liver may present with silent hepatomegaly ,they are often encountered in patients with cirrhosis who already have symptoms of the underlying disorder . these patients develop rapid increase in their liver size ,worsening of these ascites or the appearance of bloody ascites , fever pain .
Nearly 50% have elevated serum alpha fetoprtn [very high] (it non specific for this disease like other liver disease or other general disease like germ cell tumor or other tumor but if it is very high more than 1000unit per ml this only occur with hcc ).
The overall prognosis is grim but better for individuals with a signal tumor less than 2 cm in diameter ….


Huda awamleh .
14-2-2011
Monday
God bless u …