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periportal necrosis and centrilobular necrosis - sk8432
#1
can anyone explain causes of these two and why does MTX toxicity cause peiportal whereas ccl4 toxicity causes centrilobular necrosis!!thanks
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#2
Carbon tetrachloride FRs (check Goljan chapt 2)
a. CCl4 is used as a solvent in the dry cleaning industry.
b. Cytochrome P450 system in the SER converts CCl4 into a FR.
c. FRs produce liver cell necrosis with fatty change.
Production of free radicals from drugs (e.g., acetaminophen, see later), tissue hypoxia
(e.g., shock, CO poisoning), and alcohol-related fatty change of the liver (see later) initially
damage zone III hepatocytes, which, owing to their relative lack of O2, are more susceptible to
injury - will give centrilobular necrosis
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#3
P450 system located in Zone III - also that is why CCl4 - causes damage of Zome III
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#4
not sure about MTX -

thats what i found http://theoncologist.alphamedpress.org/c...2/162.full

MTX binds tightly to dihydrofolate reductase, blocking the reduction of dihydrofolate to its active form, tetrahydrofolic acid. Tetrahydrofolic acid is essential for the one carbon transfer reactions required for the synthesis of thymidylate, a precursor to DNA, and the purines adenosine and guanosine, precursors of both DNA and RNA. In standard doses, MTX is excreted unchanged in the urine. In high doses, it is partially metabolized by the liver to 7-hydroxymethotrexate [69]. When used in high doses with leucovorin rescue, MTX diffuses into both normal and malignant cells. Leucovorin enters normal cells, blocking the effects of MTX.

When MTX was used for maintenance therapy in children with acute leukemia, it led to the development of hepatic cirrhosis and fibrosis [70-72]. Fatty change, focal hepatitis, or portal fibrosis in previously untreated patients made the evaluation of MTX's role in the production of hepatotoxicity difficult.

Elevations of aminotransferases and serum lactate dehydrogenase (LDH) are quite common following high-dose MTX therapy, with an incidence of 14.1% in one report of treatment of gestational trophoblastic disease [73]. The enzymes rise with each course and are higher in patients treated with a daily schedule than in those treated on an intermittent schedule. These abnormalities resolve within one month after the cessation of therapy. High-dose MTX therapy results in acute aminotransferase elevation that is transient, reversible, and, at least in children, does not result in chronic liver disease [74].

Patients with RA or psoriasis who received cumulative doses of less than 2 g of MTX had a low incidence of hepatotoxicity, even though the average duration of therapy ranged from 28 to 48 months [75-78]. In summary, chronic low-dose MTX may lead to fibrosis/cirrhosis, while high-dose may cause altered liver function tests.

There are two case reports of the development of hepatocellular carcinoma following MTX-induced fibrosis: in a child with acute lymphoblastic leukemia and a patient heterozygous for α-1 antitrypsin deficiency, raising the additional question of long-term carcinogenesis with the use of this agent [79, 80].
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#5
MTX early path cause damge of lysosomal/ mitochochoral and hyperplasia stellate and bile duct and later you see inflammation/Kupffer cell hypErplasia that mark by macrovesicular steatosis ALSO SEEN zone III.-> You see CHICKEN WIRE ( periportal-> extension parenchyma )
The rest u can read on Goli
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#6
thank you verymotivatedlearner and cardio69
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#7
thanks for the q and answer
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