Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
?
Urea
Mitochondrion
Acetaldehyde Acetaldehyde Acetate
NAD NADH
H20
GSSG GSH Electron
Per
H20 o transport
NADP
xisome
chain
H20 H202 Catalase O2 H
OH˙ H2O2
10 MEOS H
2
Metabolites O2̇ Citric
O2 acid
NADPH cycle
Endoplasmic CO2
reticulum NADH
Fatty
H Ketones Ketosis
ADH acids
Drugs and
steroids NAD α glycerophosphate
Ethanol
Fatty liver
Lyso
Hypoglycemia Pyruvate Lactate Collagen Triglycerides
so
me
?
Hyperlipemia
Alcohol dehydrogenase
(ADH)
Ethanol + NAD ⎯⎯⎯⎯⎯⎯⎯⎯⎯→ Acetaldehyde
+
+
+ NADH + H
Microsomal ethanol
oxidizing system (MEOS)
Ethanol + NADPH + H + O2 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯
→ +
+
Acetaldehyde + NADP + 2H 2 O
Figure 4-2 Alcoholic fatty liver. This liver is markedly enlarged (3300 g)
and is yellow and greasy on external examination and cut section The MEOS is cytochrome P450-dependent, with its
due to virtually all of the hepatocytes containing macrovesicular fat.
enhancement contributing to alterations of the metabo-
lism of certain drugs. For example, significant liver cell
Clinical and biologic behavior injury can occur with the ingestion of as little as 2 g of
1. Fatty change is the most common hepatic morphologic acetaminophen (as opposed to approximately 10 g in the
feature in an alcoholic and is seen in over 90% of biopsy non-alcoholic).
and autopsy specimens in these patients.
2. There are three important pathways in alcohol metabo- Catalase
lism (refer to Fig. 4-1): Ethanol + H 2 O 2 ⎯⎯⎯⎯→ Acetaldehyde + 2H 2 O
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 73
Figure 4-3 Alcoholic fatty liver. Macrovesicular fatty change is Figure 4-4 Alcoholic fatty liver. The terminal hepatic (central) venule
seen. The terminal hepatic (central) venule in the center of the field shows no evidence of perivenular or intraluminal fibrosis. Macrove-
is unremarkable. sicular fatty change is abundant (trichrome).
A B
Figure 4-5 Alcoholic fatty liver. A, Two lipogranulomas are seen amongst the hepatocytes that contain macrovesicular fat. B, High power
shows a lipogranuloma to be composed of lymphocytes and histiocytes, many of the latter containing small fat vacuoles.
A B
Figure 4-6 Alcoholic fatty liver, enlarged mitochondria. A and B. Megamitochondria are seen within many of the hepatocytes in these low
and high power fields. These mitochondria are the same size or larger than the liver cell nucleus and are distinctly round and eosinophilic.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
74 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
This process occurs in the peroxisomes. Acetaldehyde is 7. Increased fat in the liver is noted on ultrasound examina-
further metabolized in the mitochondria to acetate and tion, where an increased echotexture is seen. On com-
then secreted. The acetaldehyde itself is toxic and causes puted tomography (CT) scans, decreased density of the
variable degrees of mitochondrial distortion as well as liver is characteristic of fatty change, which sometimes
impairment in microtubular function, contributing in can be focal in nature.
part to the enlargement of the mitochondria (megamito-
chondria) as well as the hydropic ballooning change of the Treatment and prognosis
hepatocytes seen in alcoholic liver disease. 1. Simple fatty change is asymptomatic. The fat will disap-
3. The degree of fat approximately varies with the amount pear in a severely fatty liver within 8 weeks of abstinence
of alcohol intake and to some extent the quantity of pro- of alcohol.
tein in the diet.
4. Alcohol stimulates collagen formation. Although stains
for collagen may not demonstrate sinusoidal collagen Perivenular Alcoholic Fibrosis
in simple fatty change, chemical analysis of these liv-
ers shows moderate increases in hydroxyproline, a major (Figs. 4-9 and 4-10)
amino acid found in collagen fibers.
5. Fat is generally graded as 1+, involving up to 25% of hepa- Major morphologic feature
tocytes; 2+, 25% to 50% of hepatocytes; 3+, 50% to 75% 1. Thickening of the fibrous rim surrounding the terminal
of hepatocytes, and 4+, greater than 75% of hepatocytes. hepatic (central) venules is present, with extension into
6. Hepatomegaly is usually the only abnormality on physical the perivenular sinusoids often occurring to variable
examination and most often resolves over several weeks degrees.
with abstinence of alcohol intake. Mild elevations in 2. Thin intraluminal fibrosis of these vessels is also seen.
serum aminotransferases are frequently noted but hepatic
synthetic function is normal. Other features
1. Variable degrees of macrovesicular fatty change are seen
predominantly within the perivenular zone.
2. Enlarged mitochondria (megamitochondria, refer to earlier
discussion under Alcoholic Fatty Liver) may be present in
the perivenular zone in a minority of cases.
3. Necroinflammatory change, the inflammatory cells
chiefly mononuclear, is seen but is usually mild.
4. Mallory bodies may be present but are few in number, and
when seen are more often present in the perivenular zone.
If abundant, superimposed acute alcoholic liver injury
(refer to discussion under Alcoholic Hepatitis) is also present.
5. The portal tracts exhibit only a mild lymphocytic infiltrate.
6. Interlobular bile ducts are normal to only slightly
increased in number; however, proliferating bile ductules
(metaplastic ducts ) may also be seen at the border of the
portal tracts and parenchyma.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 75
7. Variable degrees of portal fibrosis are often present, mani- 3. Long-standing right-sided heart failure: Perivenular fibrosis
fested by widening of the portal tracts with variable peri- may be seen in this condition due to prolonged perivenu-
portal intrasinusoidal collagen deposition. lar ischemia. Variable but often prominent perivenular
8. The degree of perivenular collagen deposition may in sinusoidal dilatation and congestion with liver cell atro-
some instances be striking, with marked intraluminal phy also are seen in right-sided heart failure. Fatty change
sclerosis and vascular occlusion of the small outflow ves- and megamitochondria are not features associated with
sels (“phlebosclerosis” and “veno-occlusive” changes) as heart failure.
well as variable degrees of lymphocytic infiltrates involv- 4. Veno-occlusive disease (VOD): The intraluminal fibrosis of
ing the intima and wall (“lymphocytic phlebitis”). The the terminal hepatic venules seen in VOD is morphologi-
fibrosis also extends to and involves the larger terminal cally similar to the intraluminal sclerosis seen in chronic
hepatic veins and sublobular veins. alcoholic liver disease (termed “veno-occlusive changes”);
Note: Virtually all of the morphologic features described however, in true veno-occlusive disease (refer to discussion
above are also seen in alcoholic fibrosis and cirrhosis in Chapter 6) there is considerable endothelial damage of
and in biopsies from patients having bouts of alcoholic the terminal hepatic venules, with sloughing and loss of
hepatitis. the endothelial cells, features not present in the perivenu-
lar damage seen in chronic alcoholic liver disease.
Special stains
1. Masson trichrome, Sirius Red: The perivenular and peri- Clinical and biologic behavior
portal intrasinusoidal collagen stains bright blue and red, 1. The importance of this lesion, as opposed to simple alco-
respectively. In addition, the Masson trichrome stain is holic fatty liver, is that its presence in the early stages sig-
helpful in identifying the enlarged mitochondria, which nals almost certain progression to cirrhosis if the patient
stain bright red. does not abstain from drinking.
2. Reticulin: The perivenular and periportal intrasinusoidal 2. This lesion has also experimentally been induced in
collagen deposition can be appreciated by the reticulin baboons fed alcohol.
condensation. 3. The fibrosis occurs as a result of activation and conver-
3. Verhoef-van Gieson: The sclerosis of the terminal hepatic sion of the mesenchymal stellate cells (Ito cells, fat-storing
venules can be highlighted by this elastic tissue stain. cells) seen in the perisinusoidal space to transitional cells
and eventually fibroblasts and myofibroblasts in the peri-
Differential diagnosis venular zone. This then results in the synthesis of type
1. Non-alcoholic steatohepatitis: This liver disease exhibits fat III collagen in the perivenular extracellular matrix in the
and perivenular sinusoidal collagen deposition and may space of Disse.
be indistinguishable from alcoholic perivenular fibrosis 4. Patients are usually asymptomatic at the early stage of the
on histologic grounds alone. Clinical correlation is neces- disease, with only mild abnormalities in the aminotran-
sary for distinction. ferase activities, the AST value only slightly elevated with
2. Drug-induced liver cell injury (e.g., amiodarone; refer to the ALT value usually normal.
Table 5-6, Fatty change): Certain drugs may elicit not only
fatty change but also intrasinusoidal collagenosis. Clinical Treatment and prognosis
correlation with examination of the time frame of drug 1. Abstinence of alcohol prevents progression of the disease.
usage and the onset of abnormal liver tests is important In addition, partial and sometimes complete resolution of
in diagnosis. the fibrosis also may occur.
A B
Figure 4-10 Perivenular alcoholic fibrosis. These two terminal hepatic venules from the same specimen show extensive perivenular as well
as intraluminal fibrosis, with total occlusion of the lumen on the (A) trichrome and (B) H&E stains.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
76 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Acute Alcoholic Liver Disease 3. Lipogranulomas may be seen in the perivenular zone as a
response to rupture of liver cells distended with fat, and
consist of coalescent extracellular fat droplets eliciting a
Acute Alcoholic Fatty Liver (Steatosis) mild lymphocytic and histiocytic reaction. Multinucle-
With or Without Cholestasis ated giant cells are uncommon.
4. Some degree of microvesicular fat may also be present at
(Figs. 4-11 through 4-13) times but is less common.
5. Usually round but occasionally spindle-shaped inclusions
Major morphologic features may be seen within the liver cell cytoplasm in a minority
1. Prominent macrovesicular fatty change is present and of cases, are most prominent in the perivenular zone, and
involves all zones, with greater than 75% of the hepato- represent enlarged mitochondria (megamitochondria, refer
cytes involved. to discussion under Alcoholic Fatty Liver).
2. Cholestasis may be present, with accentuation in the 6. Portal tracts may be normal in size or exhibit a mild peri-
perivenular zone (zone 3 of Rappaport). portal fibrosis.
7. Only a mild lymphocytic infiltrate with occasional neu-
Other features trophils is seen within the portal tracts, with interlobular
1. Sinusoidal collagen deposition is minimal to absent. bile ducts normal to only minimally increased in number.
2. Focal necrosis and hepatocytolysis may be present but are 8. Occasionally proliferating ductules (metaplastic ducts) may
usually mild. be present at the border of the portal tracts and parenchyma.
Special stains
1. PAS after diastase digestion (DiPAS): This stain highlights
areas of necroinflammatory change by demonstrating
increase in lysosomal activity and ceroid pigment within
Kupffer cells and macrophages within the areas of injury.
2. Masson trichrome: Thin blue strands of perivenular sinu-
soidal collagen are more readily identifiable, although the
degree of this type of collagen laydown is generally mild.
In addition, megamitochondria stain bright red.
Differential diagnosis
1. Non-alcoholic steatohepatitis (NASH): NASH contains
abundant fat, variable necroinflammatory change, and
both portal, periportal and perivenular fibrosis, and may
mimic to some degree acute alcoholic fatty liver disease.
Perivenular collagen deposition is quite uncommon
in acute alcoholic fatty liver, while cholestasis is quite
unusual in NASH. In addition, NASH often contains
Figure 4-11 Acute alcoholic fatty liver. This low power image shows numerous glycogenated nuclei, a feature that is not com-
a portal tract with periportal arachnoid fibrosis. The parenchyma
shows 100% of the hepatocytes filled with macrovesicular fat.
monly seen in acute alcoholic fatty liver.
Figure 4-13 Acute alcoholic fatty liver with cholestasis. Bile both
Figure 4-12 Acute alcoholic fatty liver with cholestasis. Abundant within liver cell cytoplasm as well as within dilated biliary canaliculi
macrovesicular fat is seen. Cholestasis is also evident with bile plug is evident on this iron stain, which uses the eosin counterstain to
formation. enable the bile to stand out better than on the routine H&E stain.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 77
Alcoholic Hepatitis
Other changes
1. Portal tracts show variable degrees of fibrosis, with prom-
inent periportal “arachnoid” fibrosis (periportal intrasinu-
soidal collagen deposition) occurring.
2. Portal mixed inflammatory infiltrates consisting of Figure 4-15 Alcoholic hepatitis. The perivenular zone shows exten-
sive intrasinusoidal collagen deposition with almost total sclerosis
lymphocytes and numerous neutrophils are seen, these and occlusion of the terminal hepatic venule. Some of the adjacent
inflammatory cells not directly oriented to any particular hepatocytes are hydropic and contain Mallory bodies (upper right
portal structures. corner of the field ).
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
78 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
A A
B B
Figure 4-16 Alcoholic hepatitis. A and B. These medium and high Figure 4-18 Alcoholic hepatitis. A, Numerous Mallory bodies are
power fields both show hydropic hepatocytes containing an eosino- seen. In addition, a prominent neutrophilic infiltrate is present, many
philic ropey intracytoplasmic material representing Mallory bodies. of these neutrophils surrounding the hepatocytes containing Mal-
lory bodies (“satellitosis”). B, Immunoperoxidase stain for Mallory
bodies. The Mallory bodies stain strongly positive with ubiquitin, as
seen in this example.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 79
A B
Figure 4-22 Alcoholic hepatitis. A, A prominent lobular neutrophilic infiltrate is present. Often the neutrophils can be seen surrounding hepa-
tocytes containing Mallory bodies. B, The neutrophilic infiltrates within the lobules can at times be quite prominent, usually associated with
a marked leukocytosis.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
80 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Differential diagnosis
1. Non-alcoholic steatohepatitis (NASH): Fatty change,
perivenular sinusoidal collagenosis, and Mallory bod-
ies are seen in both alcoholic hepatitis and the more
severe cases of NASH. The numbers of Mallory bod-
ies in NASH are usually, but not always, less than the
number seen in alcoholic hepatitis. Mallory bodies sur-
rounded by neutrophils (satellitosis) are often present in
alcoholic hepatitis but less commonly seen in NASH.
Glycogenated nuclei are more often present in NASH
than in alcoholic hepatitis. In addition, portal neutro-
phils, portal ductular proliferation, and cholestasis are
not characteristic of NASH but are frequent in alco-
holic hepatitis. Finally, a useful biochemical marker is
the serum AST:ALT ratio, which is usually greater than
2:1 in alcoholic hepatitis but is equal to or less than 1 in
NASH. Table 4-2, under the discussion of Non-Alcoholic
Figure 4-25 Alcoholic hepatitis. The portal tract is fibrotic and Fatty Liver Disease at the end of this chapter, compares
exhibits a prominent mixed inflammatory infiltrate consisting of lym-
phocytes and numerous neutrophils. Bile duct and cholangiolar pro- the two disorders.
liferation are also seen. 2. Other conditions where fat, Mallory bodies and lobular
inflammation (steatohepatitis) may be present: Wilson
disease, Indian childhood cirrhosis, chronic cholestatic
disorders (primary biliary cirrhosis, primary sclerosing
3. Bile duct proliferation is present, with proliferating chol- cholangitis), certain drugs (amiodarone), and hepato-
angioles (metaplastic ducts ) often prominent. cellular carcinoma are just a few of the disorders that
4. Perivenular cholestasis may be seen. may exhibit Mallory bodies (refer to Table 4-3, Liver
5. Megamitochondria (enlarged mitochondria) are sometimes disorders morphologically resembling alcoholic and non-
identified within the hydropic perivenular hepatocytes. alcoholic fatty liver disease, at the end of this chapter).
6. Mixed lobular necroinflammatory change is present, Usually these disorders do not contain the same degree
the inflammatory cells consisting predominantly of of sinusoidal collagen deposition and numbers of Mal-
neutrophils. lory bodies as that seen in alcoholic hepatitis. Other
7. Sinusoidal leukocytosis is often seen, associated with morphologic features as well as clinical and labora-
elevated white blood cell counts in the majority of tory correlation will usually make the distinctions more
patients. apparent.
8. A variant of this disorder that is severe and seen mostly
in autopsy specimens shows marked perivenular hydropic Clinical and biologic behavior
ballooning change of the hepatocytes with lysis of the cell 1. A subset of patients with alcoholic liver disease develop
membranes, the cytoplasm usually also containing Mal- an acute or subacute and virulent form of inflammatory
lory bodies (lytic necrosis). injury (“alcoholic hepatitis”) with a substantially worse
9. The degree of periportal and perivenular fibrosis var- prognosis and outcome.
ies, with eventual bridging fibrosis and a micronodu- 2. Patients with alcoholic hepatitis present with a broad
lar cirrhosis eventually occurring in the patient who range of clinical and biochemical abnormalities. In
continues to drink (refer to discussion under Alcoholic mild disease, patients are asymptomatic, but in severe
Cirrhosis). cases, jaundice, ascites, and hepatic encephalopathy are
present leading to increased mortality. Hepatomegaly,
Special stains hepatic pain and tenderness, leukocytosis (rarely as high
1. Masson trichrome: Sinusoidal collagen fibers and sclero- as 100,000/cm3), fever, and hepatic systolic bruits are
sis of the terminal hepatic venules are accentuated by the frequently present.
blue staining pattern. Mallory bodies also stain either 3. Serum total and direct bilirubin are elevated, serum
bright red or blue, dependent on the age of the Mallory albumin values are depressed, and prothrombin time is
bodies. Megamitochondria stain red. prolonged, markedly so in severe cases. Alkaline phos-
2. Mallory’s phloxine: Mallory bodies in their early stage phatase elevation is variable. AST is elevated, usually
stain intensely red, while older Mallory bodies stain pink in the 100 to 300 IU/L range, but ALT is substantially
or are colorless. lower and in some cases is normal.
4. Technetium sulfur colloid liver-spleen scan demon-
Immunohistochemistry strates marked redistribution of the isotope to the spleen
1. Ubiquitin, pancytokeratin: The intermediate filaments and bone marrow, with little if any uptake within the
that are an important component of Mallory bodies stain liver. Isotope flow scan shows increased hepatic arterial
intensely. flow in a large proportion of cases.
2. Horseradish peroxidase (PAP): Mallory bodies nonspecifi- 5. For unclear reasons, a worsening of the clinical and lab-
cally are bound by the peroxidase anti-peroxidase (PAP) oratory parameters 2 to 4 weeks after cessation of alco-
reaction. hol may be seen.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 81
6. Mallory bodies are a principal morphologic feature seen in c. Alcoholic fatty liver may be predisposed to injury,
hepatocytes. Although present in over 20 liver disorders, and the effect of these inflammatory cytokines
it is seen most commonly and abundantly in alcoholic and lipopolysaccharides results in alcoholic hepa-
hepatitis. Mallory bodies are filamentous randomly ori- titis. Recent evidence suggests that IL-17 may be
ented intracytoplasmic processes composed of various increased in alcoholic liver disease. Activation of
polypeptides and cytokeratins. Its origin is secondary IL-17 receptors (expressed on a variety of endothe-
to damage of the intermediate filaments by alcohol, and lial cells and fibroblasts) results in overexpression of
can be divided into three ultrastructural variants: CXC chemokines (CXCL1, CXCL6, and CXCL8),
a. Type I: Parallel array of the filaments IL-6, and adhesion molecules. This leads to activa-
b. Type II: Randomly oriented filaments tion and mobilization of neutrophils, a character-
c. Type III: Amorphous and granular, few filaments seen istic feature seen in the liver biopsies of alcoholic
7. Different staining patterns of Mallory bodies are seen hepatitis. These interesting findings require confir-
on trichrome stain (red or blue) and may be related to mation from further studies.
different subtypes or age of the Mallory bodies. The
Mallory bodies themselves can nicely be demonstrated Treatment and prognosis
by the ubiquitin immunoperoxidase stain. 1. General measures include abstinence, nutritive support,
8. The dense deposition of collagen fibers (predominantly and treatment of ascites and hepatic encephalopathy.
type III) that are most marked in the perivenular sinu- Bacterial infections of the ascites and the respiratory and
soids causes partial or complete obliteration of the urinary tracts are treated with appropriate antibiotics.
terminal hepatic venules, with obstruction to hepatic 2. A number of empiric treatments have been tried. In some
venous outflow and consequent post-sinusoidal portal controlled trials with corticosteroids, short term mor-
hypertension. bidity and mortality were unaffected, although it was
9. With abstinence, the new collagen fibers may be bro- suggested that a subgroup of severely ill patients with
ken down by collagenase and ultimately resorbed; how- encephalopathy may benefit.
ever, continued deposition of periportal and perivenular 3. The development of renal failure (hepatorenal syndrome),
collagen in the active alcoholic leads to portal‑portal encephalopathy nonresponsive to therapy, or progressive
and portal‑perivenular bridging fibrosis and eventual increase in the prothrombin time are all associated with a
cirrhosis. poor outcome (80% mortality).
10. Some of the pathophysiologic processes are the following: 4. Liver transplantation is not generally considered because
a. Immune dysregulations occur, which include of increased mortality related to sepsis, pancreatitis and
enhanced innate immunologic responses such as cyto- poor nutritional state, and the potential for recidivism.
kine release (IL1β), tumor necrosis factor (TNFα, These patients are too ill to complete an alcohol reha-
IL6), chemokines (IL8), and adaptive immune bilitation program, which is usually recommended for a
response to acetaldehyde protein adducts. period of 6 months, a desired requirement in all trans-
b. The specific mechanisms are not clear but it is postulated plant candidates with substance abuse.
that ethanol increases intestinal permeability, permitting
bacterial lipopolysaccharide (endotoxin) to access the
liver and activate the Kupffer cells, which leads to the Alcoholic Foamy Degeneration (AFD)
secretion of inflammatory cytokines (e.g., TNFα) and
which may contribute to the formation of hepatic fat. (Figs. 4-26 and 4-27)
A B
Figure 4-26 Acute foamy degeneration, alcoholic etiology. A, The hepatocytes in the perivenular and midzones are enlarged and filled by
predominantly fine droplet microvesicular fat (foamy degeneration). Few inflammatory cells are seen. B, High-power view shows the numer-
ous microvesicles in each liver cell. Frequently the liver cell nucleus is in the center of the cell and is surrounded by fine droplet fat, as opposed
to hydropic swelling of the hepatocytes whereby the nucleus is often peripherally located.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
82 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Differential diagnosis
1. Other causes of microvesicular fat. Various conditions,
most notably acute fatty liver of pregnancy, Reye syn-
drome, injury secondary to certain drugs (e.g., tetracy-
cline, valproic acid), and non-alcoholic steatohepatitis
(NASH) may also be associated with microvesicular
steatosis. In acute fatty liver of pregnancy, the fatty
Figure 4-27 Acute foamy degeneration, alcoholic etiology (elec- change usually resolves after delivery, and Reye syn-
tron microscopy). The cytoplasm of the hepatocyte is filled with drome is only rarely seen in adults. NASH usually
numerous small droplets of fat (neutral triglycerides). Occasional
slightly larger fat droplets are also seen. The nucleus is small and
contains macrovesicular fat, although microvesicular
centrally oriented within the cell. (From Uchida T, et al. Alcoholic changes in some instances may be prominent; in addi-
foamy degeneration—a pattern of acute alcoholic injury of the liver. tion, glycogenated nuclei are commonly seen in NASH
Gastroenterology 1983;84:683-692, with permission from Elsevier.) but are infrequent in alcoholic foamy degeneration.
Certain drugs such as valproic acid may be associated
with microvesicular fat, but may also show perivenular
liver cell necrosis. The time frame of drug usage and
Major morphologic features liver test abnormalities is important in the differential
1. Perivenular and often midzonal hepatocytes contain diagnosis.
abundant fine droplet (microvesicular, “foamy”) fat.
Clinical and biologic behavior
Other features 1. Patients with alcoholic foamy degeneration present
1. Portal tracts show variable degrees of portal fibrosis and with an acute onset of hepatomegaly (90%), jaundice
periportal sinusoidal collagen deposition (“arachnoid” (90%), and abdominal pain (59%). Ascites is usually
fibrosis). absent.
2. Only a mild predominantly lymphocytic portal inflam- 2. Serum ALT ranges between 100 to 300 IU/L, though
matory infiltrate is seen, associated with only mild bile rarely may be as high as 700 IU at initial presentation.
ductular proliferation. Neutrophils may be present but are AST levels of 100 IU are usually seen. The transaminase
uncommon. pattern may initially suggest viral hepatitis or mechanical
3. Although focal lobular necroinflammatory change may bile duct obstruction, although the AST:ALT ratio would
be seen, usually the degree of inflammation is quite mild support an alcoholic etiology.
and is usually composed of mononuclear cells. 3. Hyperbilirubinemia, sometimes as high as 20 mg/dL,
4. Macrovesicular fat is almost always present to some is seen, with serum albumin and prothrombin time
degree as well, and is seen predominantly within the mildly abnormal. The white blood cell count is usually
midzone and periportal zone; however, individual peri- normal.
venular hepatocytes may exhibit both macrovesicular and 4. Ultrastructural features of foamy cells show striking dam-
microvesicular fat. age and loss of organelles, with diffuse distribution of fine
5. The nuclei of the “foamy” hepatocytes are most often fat droplets
centrally located within the cytoplasm and appear slightly 5. Microvesicular fat may resolve shortly after hospitaliza-
smaller than nuclei seen in the “normal” liver. tion. Liver biopsy may only reveal macrovesicular fatty
6. Megamitochondria are sometimes found within the change with the diagnosis of acute foamy degeneration
foamy hepatocytes. missed.
7. Some degree of cholestasis may be present but is not common. 6. In very severe cases, almost only seen at autopsy, adja-
8. Mallory bodies and perivenular sinusoidal collagen cent cell membranes may rupture (“lytic necrosis”). These
deposition are not seen in the “pure” form of alcoholic cases often have Mallory bodies as well but without a
foamy degeneration; however, often foamy hepatocytes neutrophilic infiltrate.
are present in livers also exhibiting Mallory bodies and 7. Four percent of all patients dying from alcoholic
perivenular sclerosis (“mixed” forms of alcoholic foamy liver disease will exhibit foamy degeneration of
degeneration and alcoholic hepatitis). hepatocytes.
8. Microvesicular foamy hepatocytes and changes of alco-
Special stains holic hepatitis with Mallory body deposition may be
1. Oil red O: The hepatocytes containing the microvesicu- prominent morphologic features in the same biopsy, rep-
lar foamy fat may appear “hydropic” on routine hema- resentative of the wide spectrum of changes seen in acute
toxylin-eosin (H&E) stain in many cases, and hence alcoholic liver disease.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 83
B
Figure 4-30 Alcoholic cirrhosis (active drinker). A, The regenera-
Figure 4-29 Alcoholic cirrhosis. This high power image shows the tive nodule is small (“micronodular”), poorly demarcated, and con-
yellow-tan nodules to measure up to 2 mm in greatest dimension tains mild macrovesicular fatty change. B, Higher power shows
(“micronodular”). This feature is uniformly present within all of the prominent deposition of periseptal intrasinusoidal collagen. Moder-
hepatic lobes. ate macrovesicular fatty change is also present (trichrome).
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
84 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
A B
Figure 4-31 Alcoholic cirrhosis (active drinker). A, The parenchyma shows poorly demarcated nodules (pseudolobules) without appreciable
regenerative change. B, Higher power demonstrates hepatic trabecular cords without any hydropic or regenerative changes. Intrasinusoidal colla-
gen deposition in the periseptal regions is seen. These features are characteristically present in biopsies from alcoholics who are actively drinking.
A B
Figure 4-34 Alcoholic cirrhosis (abstinence of alcohol intake). A, The cirrhotic liver on the trichrome stain shows sharply demarcated fibrous
bands with well-developed regenerative nodules. No fatty change or sinusoidal collagen deposition is present. B, A small regenerative nodule
surrounded by dense fibrous septa is seen in this example of advanced inactive alcoholic cirrhosis.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 85
Figure 4-35 Alcoholic cirrhosis (abstinence of alcohol intake). The Figure 4-36 Alcoholic cirrhosis. The sublobular vein shows fibro-
fibrous band in this example shows a mild lymphocytic infiltrate and intimal thickening (phlebosclerosis) with mild lymphocytic infiltrates
mild bile duct proliferation. The parenchyma demonstrates hepatocytes within the intima (lymphocytic phlebitis). The sclerosis at times can
without fatty change, the cells forming distinct cords and sinusoids be striking, with total occlusion of the entire lumen (trichrome).
without an inflammatory infiltrate or sinusoidal collagen deposition.
fat, sinusoidal collagen, and Mallory bodies by 3 to 6 in some instances the regenerative nodules in NASH
months of abstinence. The fibrous septa between these can be well-demarcated as opposed to the poorly formed
nodules may eventually become quite thin when the nodules in the active alcoholic. NASH also is associated
alcoholic stops drinking and the cirrhosis is at an early with the presence of glycogenated nuclei, a feature less
stage. commonly seen in the alcoholic.
6. Prominent sclerosis is seen involving the terminal 2. Wilson disease: Fat, sinusoidal collagen deposition, Mal-
hepatic venules and veins that are entrapped within the lory bodies, and cirrhosis may be seen in Wilson disease.
fibrous bands. In addition, intraluminal sclerosis of the Special stains for copper (rubeanic acid, rhodanine) and
terminal hepatic and sublobular veins is evident. copper-binding protein (orcein) show strong staining in
7. Cholestasis may be present in the advanced stages. Wilson disease, as does hepatic tissue copper quantitation.
8. Diffuse interstitial fibrosis may be seen in the active alco- 3. Chronic viral hepatitis secondary to HCV: Chronic hepati-
holic, with intrasinusoidal collagenosis involving virtu- tis C is associated with variable degrees of fat and sinu-
ally all of the sinusoids, without regenerative changes of soidal collagen deposition, but the degree seen is typically
the hepatocytes. much less than in the active alcoholic. In addition, Mal-
9. As the cirrhosis progresses, the fibrous septa become lory bodies are not features in chronic HCV infection.
exceptionally wide in the active alcoholic, with the dense Of note is that it is not uncommon for chronic alcoholics
scars most evident at the junction of the right and left with liver disease to also be HCV positive, hence sero-
hepatic lobes. logic assessment is important in the differential diagnosis.
10. Hepatocellular carcinoma (HCC) may be seen as a sec- 4. Drug-induced liver injury: Certain drugs can cause fat,
ondary change in anywhere from 4% to 10% of patients variable sinusoidal collagen deposition, and in some
with advanced disease, usually occurring in patients who instances Mallory bodies (e.g., amiodarone; refer to
have stopped drinking and hence survived longer than the Tables 5-6, Fatty Change, and 5-8, Mallory Bodies). Clini-
active alcoholic. Those patients with co-existing chronic cal correlation is important in the differential.
HCV are at a higher risk of developing HCC as well. 5. Indian childhood cirrhosis: This liver disease is associated
with a micronodular cirrhosis, sinusoidal collagenosis, and
Special stains numerous Mallory bodies. This disorder, however, devel-
1. Masson trichrome: The sinusoidal collagen deposition and ops in infancy, with liver failure and death by 2 years of
fibrous bands are best appreciated. age.
2. Perl’s iron : Increase in stainable iron is sometimes appar- 6. α1-Antitrypsin deficiency: In the adult, a well-established
ent within periseptal hepatocytes. cirrhosis may occur in this hepatic disorder, with vari-
able degrees of fat and rarely Mallory bodies identified.
Immunohistochemistry The presence of α1-antitrypsin globules in the periseptal
1. Ubiquitin, pancytokeratin: These stains are useful in confirm- hepatocytes on DiPAS stain and confirmed on immuno-
ing the presence of Mallory bodies in the active alcoholic. peroxidase stain is diagnostic; however, of note is that in
the heterozygous states (PiMZ), patients may have inclu-
Differential diagnosis sions without liver disease. Therefore, when cirrhosis and
1. Non-alcoholic steatohepatitis (cirrhotic stage) (NASH): This α1-antitrypsin inclusions are seen in a patient with a long
liver disease in the cirrhotic stage can mimic alcoholic cir- history of alcohol abuse, phenotyping is essential to bet-
rhosis. Usually the degree of fat in NASH at this stage is ter define the etiology of the cirrhosis (refer to the section
significantly less than in the active alcoholic. In addition, under α1-Antitrypsin Deficiency in Chapter 8).
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
86 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 87
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
88 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
A B
Figure 4-38 Non-alcoholic steatohepatitis. A, The trichrome stain shows abundant sinusoidal collagen involving the terminal hepatic venule
and extending into the adjacent parenchyma. B, The perivenular zone on H&E stain shows prominent intrasinusoidal collagen deposition with
liver cell ballooning, Mallory body formation, and a moderate predominantly neutrophilic infiltrate.
Figure 4-39 Non-alcoholic steatohepatitis. The hepatocytes are Figure 4-40 Non-alcoholic steatohepatitis. Moderate macrovesicu-
hydropic, with some containing Mallory bodies. A mild predomi- lar fatty change is seen with a moderate predominantly neutrophilic
nantly lymphocytic infiltrate is seen. Sinusoidal collagen deposition infiltrate.
is prominent.
Figure 4-41 Non-alcoholic steatohepatitis. High-power shows Figure 4-42 Non-alcoholic steatohepatitis. Numerous glycoge-
numerous Mallory bodies with a neutrophilic infiltrate surrounding nated nuclei of hepatocytes are seen. Moderate macrovesicular fat
some of the cells. is also present.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 89
Other features
1. Variable degrees of periportal fibrosis are also present,
with eventual progression to a micronodular cirrhosis
in a large minority of cases. In the cirrhotic stage, the
degree of fat is often less prominent than in early stage
disease.
2. In markedly active disease, the Mallory bodies may
extend into the midzones but are seldom seen diffusely
within the lobules. In cirrhotic livers, the Mallory bod-
ies when present may be more apparent in the periseptal
regions but often are scattered within the regenerative
nodules.
3. Microvesicular fat may also be seen.
Figure 4-43 Non-alcoholic steatohepatitis. Both macrovesicular 4. Glycogenated nuclei of hepatocytes are often present and
and microvesicular “foamy” change of hepatocytes is present.
predominate in the periportal liver cells.
5. Rarely megamitochondria of hepatocytes may be
present.
6. Portal tracts show variable degrees of lymphocytic infil-
tration, with some degree of periportal interface inflam-
matory activity also apparent in some cases. Although
occasional neutrophils may be seen, they are uncommon.
7. The terminal hepatic venules may sometimes be asso-
ciated with endothelial inflammation (endothelialitis),
although this feature is uncommon.
8. The regenerative nodules in the cirrhotic stage may be
well-formed or poorly formed.
9. Non-caseating granulomas have been reported in patients
after bypass surgery for morbid obesity.
Special stains
1. Masson trichrome: The portal, periportal and perivenu-
lar fibrosis seen in non-alcoholic steatohepatitis are best
enhanced with this stain. In addition, the megamito-
Figure 4-44 Non-alcoholic steatohepatitis. An epithelioid granu- chondria can often best be seen and stain red.
loma is present within the lobule in this patient who underwent jeju- 2. Perl’s iron: A usually mild degree of stainable iron can be
noileal bypass surgery for morbid obesity.
seen in periportal hepatocytes.
A B
Figure 4-45 Non-alcoholic steatohepatitis, cirrhotic stage. A and B. Both low- and medium-power images show a well-established cirrhosis,
with the regenerative nodules small (“micronodular”). Mild periseptal sinusoidal collagen deposition can be seen in the higher power image.
The amount of fat is only mild in this example, as it is not uncommon for the degree of fatty change to decrease by the time the liver is cir-
rhotic (trichrome).
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
90 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases 91
Table 4-3 Liver Disorders Morphologically regression analysis of mean corpuscular volume, AST and
Resembling Alcoholic and Non- ALT values, height, weight, and sex to generate a score. A
Alcoholic Fatty Liver Disease score >0 (the higher the “+” score the greater the probabil-
ity) favors alcoholic liver disease, and a score <0 (the lower
MALLORY SINUSOIDAL
DISORDER BODIES COLLAGEN FAT
the “–” score, the greater the probability) favors nonal-
coholic fatty liver disease. In addition, when the amino-
Alcoholic hepatitis +++ +++ +++
transferases are >100, the AST:ALT ratio is usually ≤1
Non-alcoholic steatohepatitis +/++ ++ +++ in most but not all non-cirrhotic patients with NASH, a
(NASH)
useful clue in differentiating NASH from active alcoholic
Gastric stapling, gastric or ++ ++ +++
jejunoileal bypass
liver disease, where the ratio in the latter is usually >1.
5. On physical examination hepatomegaly is frequently
Indian childhood cirrhosis +++ ++ –
present, although the accuracy of the clinical findings is
Wilson disease +/++ + +
often in doubt because of the difficulty in palpating the
Chronic hepatitis C – + +/++ liver in an obese individual. In patients with cirrhosis,
Chronic cholestasis splenomegaly may be present. Hepatocellular carcinoma
• Extrahepatic biliary atresia + – – may develop rarely.
• Large extrahepatic bile duct + – – 6. Ultrasound scan shows hepatomegaly and increased
obstruction
• Primary biliary cirrhosis ++ – –
echotexture consistent with fatty change or fibrosis. On
• Primary sclerosing +/++ – – CT scan, findings of diffuse low density of the liver com-
cholangitis pared to the spleen density are diagnostic of fatty change.
Weber-Christian disease + – – The diagnosis can be confirmed on liver biopsy where
Abetalipoproteinemia + – – the disease can be staged by semi-quantifying steatosis,
Tyrosinemia – +/++ +/++ inflammation, necrosis, and fibrosis.
7. There are no satisfactory noninvasive tests for assessing
Glycogen storage disease 1a +/++ – +
the degree of fibrosis, but several have been proposed.
Galactosemia – +/++ ++
Cytokeratin 18 (CK18) is a major intermediate filament
α1-antitrypsin deficiency + – – protein in hepatocytes and is cleaved mainly by caspase
Kwashiorkor + – +++ 3 in the apoptosis cascade. Higher CK18 fragments
Post-intestinal resection + – – are seen in NASH, although 25% of suspected NASH
Radiation + + – patients with elevated CK18 levels have normal histology.
Asbestosis + – – The NAFLD score, utilizing BMI, AST/ALT ratio, glu-
Hyperalimentation (TPN) – ++ + cose level, platelet count and albumin level, showed that a
Tumors low cut off score had low probability of advanced fibrosis,
• Focal nodular hyperplasia + – +
whereas a high cutoff indicated significant fibrosis. The
• Liver cell adenoma + – +/++ BARD score is a weighted sum of BMI >28 (1 point),
• Hepatocellular carcinoma +/++ + + AST/ALT >0.8 (2 points) and diabetes (1 point); scores
Drugs of 2 to 4 had odds ratio predicting advanced fibrosis. The
• Perhexiline maleate + – – inclusion of age in the Fibrotest model (using three serum
• Diethylaminoethoxyhexes- + – – markers for matrix turnover) was considered to predict
trol advanced fibrosis. The clinical utility of all these indirect
• Glucocorticoids + – ++ measurements of fibrosis and their relative benefit will be
• Griseofulvin + – –
• Methotrexate +/– ++ + validated in larger cohorts of patients with NAFLD and
• Nifedipine ++ + + NASH.
• Tamoxifen + − + 8. NAFLD and NASH were also seen in patients’ status-
• Amiodarone ++ ++ + post jejunoileal bypass, a surgical procedure for producing
• Estrogens + − +
• V itamin A +/– ++ +
significant and rapid weight loss in the morbidly obese
patient. The gastrointestinal tract is shortened by anas-
Frequency in liver biopsies: +++, common; ++, occasional; +, rare. tomosing the proximal 14 inches of jejunum to the distal
4 inches of ileum, whereby patients may lose anywhere
from 65 to 127 lbs during the first 5 months after surgery.
3. NAFLD is the most common cause for asymptomatic Although most patients may just have a fatty liver on
elevation of serum transaminases and for referral to hepa- biopsy, up to 12% may develop liver disease characteristic
tologist. Elevations in ALT and AST are usually mild and of NASH. This procedure is not currently performed.
frequently less that 100 U/L. Serum bilirubin is normal, 9. The pathophysiologic concepts for NASH are reviewed
alkaline phosphatase and γ-glutamy transpeptidase activ- under the discussion above for Non-Alcoholic Fatty Liver
ities are mildly or variably elevated, and hepatic synthetic (NAFL).
function is preserved.
4. There are no specific diagnostic tests for this disease. A Treatment and prognosis
number of composite tests have been evaluated that pro- 1. There is no specific treatment for this condition. Weight
vide a greater or lower probability of diagnosis. A com- loss and an exercise program will usually lead to dis-
puterized calculation of alcoholic liver disease/NAFLD appearance of fat, particularly loss of visceral fat and
index uses a weighted multivariate model and logistic improvement in histology.
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
92 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
2. Treatment trials with ursodeoxycholic acid and vitamin E fatty acids, SAMe, exenitide, and recombinant leptin and
have been tried with no conclusive results regarding ben- endocannabinoid receptor antagonists are currently in
efit. Taurine, considered to function as a lipotrophic fac- preliminary stages of clinical trials.
tor, improves mobilization of fat and was found to reduce 3. In patients with cirrhosis progressing to liver failure, liver
hepatic fat on ultrasound in a small group of children transplantation may be performed. Recurrent disease in
treated with oral supplements. Betaine, a precursor of the graft can occur.
S-adenosylmethionine and a hepatoprotective factor, was 4. In patients who acquire the liver disease after bypass sur-
associated with improvement in liver tests and histology gery, liver biopsy should be performed. If histopathologic
after 1 year of treatment in a small pilot study. In a recent changes typical for this lesion are noted and other etiolo-
study, the thiazolidinedione drug piaglitazone was shown gies excluded, early takedown of the bypass may prevent
in a randomized controlled study to decrease serum the development of cirrhosis.
ALT, improve insulin sensitivity, and histology; however
patients on this medication developed increase in weight.
Two other studies with this type of drug showed equivo- REFERENCES
cal results. The use of metformin in NAFLD patients
who were not diabetic was shown in a meta-analysis to The complete reference list is available online at www.
decrease serum transaminases and improve histology. expertconsult.com.
Other drugs, namely silimarin, pentoxyfylline, omega 3
Downloaded for Poltekkes Kemenkes Bengkulu (ckuser.poltekkesbengkulu@gmail.com) at McGill University from ClinicalKey.com by Elsevier on July 07, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.