Practical Updates in Liver Pathology: Grading, Staging, and Nomenclature
Section 3 -
Compound Disease Occurrence and Overlap Syndromes
Neil Theise, M.D.
Romil Saxena, M.D.
56 year old man. Hepatitis C positive; liver biopsy for grading and staging
Diagnosis: Chronic hepatitis with moderate interface activity and at least
portal fibrosis, clinically hepatitis C
Steatosis, moderate with extensive steatofibrosis.
Hepatitis C infection and non- alcoholic fatty liver disease are two of the commonest causes of
chronic liver disease in the US; therefore it is not unlikely that these 2 conditions may co-exist in the
same patient. However, this simple fact is complicated by experimental evidence that implicates HCV as
an etiologic factor in the development of steatosis. In transgenic mouse models, the hepatitis C core
protein has been shown to lead to hepatic steatosis, and correlate with the grade of steatosis. The HCV
core protein has also been found within fat droplets in hepatocytes, and has been shown to inhibit
microsomal transfer protein which may lead to an accumulation of triglycerides in hepatocytes.
The original descriptions of the histological features of HCV described mild macrovesicular steatosis,
in addition to portal lymphoid follicles and bile duct damage, as one of the 3 cardinal features of HCV.
It has become clear over the years however that the association of fatty liver and hepatitis C infection
is not a simple one, especially in populations predisposed to fatty liver disease.
Several studies have shown an independent association of steatosis with infection by genotype 3, but
not with genotype 1. Sharma et al found steatosis in all patients with genotype 3; however in infection
with genotype 1, the grade of steatosis correlated with BMI. Similarly, Hofer et al found correlation of
BMI with steatosis in patients with genotype 1 infection, but not with genotype 3 infection. Monto
reported that when patients with risk factors for NASH were excluded, only genotype 3 remained an
independent predictor of steatosis. Additionally, a correlation has been demonstrated between viral load
and development of steatosis in HCV genotype 3 infection. Thus, it appears that mild steatosis seen in
non-3 genotype infection is a manifestation of NAFLD; whereas steatosis in patients with genotype 3
infection is the result of viral infection.
Sharma et al and Hofer et al have shown lower cholesterol levels in patients with genotype 3. This
lipid abnormality is reversed with viral eradication, but fails to normalize in non-responders. A direct
relationship between cholesterol levels and hepatic steatosis was however not apparent. Other studies
have shown lower beta-lipoprotein levels in patients with genotype 3 HCV, and this finding was associated
with the presence of steatosis. Furthermore, a correlation has been demonstrated between hepatic viral
load and apoprotein B levels. This raises the intriguing possibility that the hepatitis C virus may
interfere with lipid metabolism.
Several studies have shown the relationship and role of hepatic steatosis, body weight, visceral
obesity and degree of fibrosis in HCV. An additional consequence of the presence of steatosis in
association with hepatitis C infection is poor virological response of these patients to anti-HCV
therapy. This may be particularly important in the context of increasing incidence of obesity; in other
words, we may be required to treat more HCV patients with associated NAFLD.
40 year old woman with elevated alkaline phosphatase (500-700 I.U.) and positive anti-mitochondrial
antibodies, 1:640. ALT/AST also elevated in 100 - 200 I.U. range.
Diagnosis: Primary biliary cirrhosis - autoimmune hepatitis overlap
The term overlap syndrome has been applied to 2 distinct situations. The first is the crossover
patient, who has characteristics mainly of one autoimmune disease, associated with one or two features of
another: For e.g., a patient with distinctive features of PBC who also has positivity for autoimmune
markers other than AMA. This is an erroneous definition of overlap autoimmune syndromes because there is
considerable overlap in the clinical, biochemical and serological and even histological features in the
classic presentations of the hepatic autoimmune diseases. The true overlap syndromes should by
definition, show majority of the clinical, biochemical, serologic and histologic characteristics of 2
The considerable overlap of clinical, serological, biochemical and histological features that occurs
between the various autoimmune hepatic diseases makes diagnosis of the true overlap syndromes
particularly challenging. This is evident in literature where several studies fervently claim the
existence of overlap syndromes, and an equal number dispute their occurrence with comparable vigor. Thus
the existence of a PBC-AIH overlap syndrome is a matter of intense debate, since PBC may be AMA negative,
may have aberrant markers of autoimmunity, or may show considerable portal and lobular inflammation.
Titers of AMA in PBC can fluctuate, becoming either positive or negative over the course of the disease.
Up to 50% of PBC patients have low titers of ASMA and 70% are positive for ANA. Conversely, low AMA
titers have been found in approximately 20% of patients with AIH. Some patients even have antibodies
specifically against the PDC -E2 complex. Histologically, some degree of hepatitis-like parenchymal
injury is almost universal in PBC.
Using a set of strict criteria that required diagnosing each disease separately by the presence of at
least 2 of 3 criteria for each disease, the incidence of PBC-AIH overlap was found to be 9% among a
series of unselected PBC patients. At least 2 of 3 of the following criteria were required for the
diagnosis of PBC: 1) serum alkaline phosphatase levels at least 2 times the normal level or GGT levels
at least 5 times normal, (2) positive AMA and (3) a liver biopsy specimen showing florid duct lesion.
The diagnosis of AIH required at least 2 of the following 3 criteria: (1) ALT levels 5 times normal, (2)
serum IgG 2 times the normal level or a positive ASMA, and (3) liver biopsy with moderate or severe
interface hepatitis and no other disease except PBC (Chazouilleres, 1998).
A separate study defined PBC-AIH overlap syndrome as all patients who had an aggregate score of 10 or
greater on the IAHG scoring system for AIH, and seropositivity for AMA. These patients had lower levels
of IgG, higher levels of IgM and lower occurrence of ASMA than classical AIH. These patients entered
remission with steroids as commonly as patients with classical autoimmune hepatitis (Czaja, 1998).
The 2 components of PBC-AIH overlap syndrome may occur either simultaneously at presentation, or
sequentially during the course of their illness. Alternatively, PBC-AIH may appear simultaneously but
may switch to one disease or another during the course of the disease. Patients may show flares of AIH
either spontaneously or under UDCA therapy and require steroids in addition to UDCA, which can be tapered
off once normalization of transaminase levels has been achieved
Additional confusion is caused by the terms autoimmune cholangitis and autoimmune cholangiopathy,
which are used for patients who have typical features of PBC but are AMA negative. This group of
patients constituted 32% of 200 patients diagnosed with PBC at the AFIP; this incidence is probably
skewed due to the consultation nature of the practice at AFIP (Goodman, 1995). A series of 597 patients
at the Mayo Clinic found 5.8% of PBC patients to be negative for AMA by immunofluorescence (Lacerda,
1995). However, negativity for AMA depends on the technique used for its detection and many cases that
are negative by immunofluorescence may show positivity by ELISA or immunoblotting. Additionally, PDC-E2
reactivity may be positive in biliary epithelial cells, even in the absence of AMA.
In a study of 200 cases of histologically characteristic PBC, Goodman et al studied the serological
profile with respect to presence of AMA and ANA by separating them into 4 serological groups: AMA+ / ANA
- (31%), AMA+ / ANA+ (37%), AMA - / ANA + (20%) and AMA - / ANA - (12%). The authors found no
difference in clinical, laboratory or histologic features between these 4 groups, concluding that the
antibodies are merely paraphenomena of the autoimmune disease processes, and not pathogenetically
important. Subtle differences have been found between the AMA negative and AMA positive groups. AMA
negative PBC patients have been found to have positive SMA and ANA more often than AMA positive patients;
lower IgM and AST, and higher IgG than the AMA positive group. The titers for ANA tend to be higher in
AMA negative PBC. However, the preponderance of evidence suggests that autoimmune cholangitis/
autoimmune cholangiopathy is merely a subset of PBC that is AMA negative.
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- Hofer H, Bankl HC, Wrba F et al. Hepatocellular fat accumulation and low serum cholesterol in patients infected with HCV-3a. Am J Gastroenterol 2002; 97: 2880-2885.
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- Petit JM, Benichou M, Duvillard L et al. Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis and liver fibrosis. Am J Gastroenterol 2003; 98: 1150-1154.
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