Alimentary tract and pancreas

Alimentarni trakt i pankreas

1 Institute for Infectious and Tropical Diseases,

Clinical Center of Serbia, Medical Faculty

University of Belgrade

2 Department for Infectious Diseases, General

Hospital of U`ice

3 Medical Faculty University of Belgrade.

ARCH GASTROENTEROHEPATOL 2003; 22 (No 1 - 2): 12 – 17

Epidemiological and clinical

data of outpatients with

chronic viral hepatitis

Epidemiolo{ko-klini~ki podaci ambulantnih

bolesnika sa hroni~nim virusnim hepatitisom

( accepted May 29th, 2003 )

Key Words:

chronic hepatitis,

Hepatitis C Virus,

Hepatitis B Virus

Abstract

Total of 212 outpatients with chronic hepatitis were evaluated. Patients were followed-up at lest six

months to two years. Clinical, laboratory, ultrasonography examination and viral serological tests were

performed for differential diagnosis. Viral infection was discovered in 179 patients (Hepatitis C Virus,

Hepatitis B Virus, and co-infection with both viruses in 122, 56 and 1 patients, respectively). Distribution

by age confirmed more numerous young patients (from 21-30 years) in chronic hepatitis C, while majority

of patients with chronic hepatitis B, were older (from 41-50 years). The higher prevalence of male

gender was in both groups. Epidemiological data were positive in about half of patients with chronic C

hepatitis, while majority of patients with chronic hepatitis B were without known route of infection.

Most patients with chronic hepatitis C were recognized as intravenous drug abusers (48%). Analyzed

alanine aminotransferase values confirmed mild elevation in the majority of patients (45.28%), independent

of etiology. The most frequent associated disease in both groups was fatty liver of unknown

cause. Clinically, investigated patients were mostly presented as mild chronic liver disease, exceptionally,

with liver cirrhosis.

In conclusion, majorities of outpatients are young males with Hepatitis C Virus infection, mostly drug

abusers. Histology assessment of liver tissue would yield more information on differential diagnosis,

eventually associated disease, and stage of fibrosis that is crucial for disease progression.

Sa`etak

Ispitano je ukupno 212 ambulantnih bolesnika sa hroni~nim hepatitisom. Bolesnici su pra}eni od {est meseci

do dve godine. Radi diferencijalne dijagnostike, ura|ena su klini~ka i laboratorijska ispitivanja, pregled

ultrazvukom kao i virusolo{ki serolo{ki testovi. Virusna infekcija je na|ena u 179 bolesnika (hepatitis C

virus: 122, hepatitis B virus: 56, konfekcija sa oba virusa :1). U odnosu na uzrast, u bolesnika sa hroni~nim

C hepatitisom najbrojnijie su bile mla|e osobae (od 21-30 godina), dok je ve}ina bolesnika sa hroni~nim

B hepatitsom bila starija (od 41-50 godina). U obe grupe bolesnika dominirali su mu{karci. Pozitivne epidemiolo{

ke podatke je imalo oko polovine bolesnika sa hroni~nim C hepatitisom. Ve}ina bolesnika sa

hroni~nim B hepatitisom nije imala podatke o na~inu zaraze. Intravenski narkomani su bili najbrojniji

me|u bolesnicima sa hroni~nim C hepatitisom (48%). Vrednosti alanin aminotransferaze su bile umereno

povi{ene u ve}ine bolesnika (45.8%), nezavisno od etiologije. Od udru`enih bolesti, masna jetra neprepoznatog

uzroka je bila naj~e{}i nalaz u obe grupe bolesnika. Ve}ina bolesnika je imala bla`i klini~ki oblik,

ciroza jetre je bila retka. U zaklju~ku, najbrojnije ambulante bolesnike ~ine osobe sa hroni~nim C hepatitisom,

uglavnom mla|eg uzrasta i epidemiolo{kim podacima o intravenskom konzumiranju droge.

Histolo{ka procena tkiva jetre bila bi zna~ajna radi detaljnije diferencijalne dijagnoze, otkrivanja eventualnih

drugih stanja i odre|ivanja stadijuma fibroze kao najzna~ajnijeg faktora za progresiju bolesti.

Klju~ne re~i:

hroni~ni virusni hepatitis,

Hepatitis C Virus,

Hepatitis B Virus

INTRODUCTION

Chronic viral hepatitis (CVH) is a global public health

problem. Two primarily hepatotropic viruses, Hepatitis C

virus (HCV) and hepatitis B virus (HBV), are main causes of

the disease. It is estimated that approximately 400 million,

and up to 200 million of individuals in the world, suffer from

chronic viral B and C infections, respectively (1,2). Viral

transmission is mainly parenteral, sexual and perinatal.

Other ways of transmission (percutaneous and nosocomial),

occur as well (3-7). Fortunately, rigorous screening practices

diminished the risk of transmission through blood transfusion.

The pathogenesis of CVH is still unclear. Replicating in

hepatocytes, viruses are capable to produce persistent infection

and as a consequence, chronic inflammation of the liver.

Liver damage mainly stems from cellular immune response,

but many other factors can influence its clinical presentation

and final outcome (8,9). Alcohol use, male sex, age at disease

acquisition, co-infection with HBV and HIV, genetic

background, metabolic diseases (type II diabetes mellitus,

hyperlipidemia, iron overload), high body weight, even

smoking, etc., are associated with more rapid disease progression,

particularly in chronic hepatitis C (CH-C) (10-19).

Clinical course of CVH can be extremely various and is nonpredictable.

It may have a wide spectrum of features, ranging

from non-symptomatic to severe hepatitis ending to liver

cirrhosis, or even, hepatocellular carcinoma (HCC) (20-22).

Efforts to discover infection, understanding clinical manifestations

and natural history of the disease, careful monitoring

of patients, and eventually, offering antiviral therapy,

are critical to prevent progression of the disease and its serious

sequelae.

AIM OF STUDY

The aim of this study was to investigate some of epidemiological

and clinical data of outpatients in order to

characterize them as a particular group of patients with

chronic viral hepatitis. Study objectives were following:

- Estimate the etiology of chronic viral hepatitis in outpatients

- Analyze demographic data of patients comparing with

aetiology

- Identify the route of viral transmission and the risk of

infection

- Notice other diseases as co-factors that could be important

for the disease progression

- Interpret the results of ALT values as a parameter for

liver necrosis

- Evaluate the stage of the disease on the basis of clinical

picture and radiological imaging

PATIENTS AND METHODS

Total of 212 outpatients with chronic liver disease (138

males, 74 females; age range: 13-76 years) was randomly

included in this investigation from January 2000 to

December 2001. Patients were followed-up at Hepatology

Clinic at least six months to fulfill criteria of chronic hepatitis.

Participants were pending for liver biopsy, although some

of them refused it or had relative or absolute contraindications.

They were not hospitalized, nor received antiviral therapy

before the investigation. All analyzed parameters were

taken retrospectively, including demographic data, behavioral

and other risk of infection, alcohol or drug consumption,

symptoms of the disease, and clinical findings. As well, routine

laboratory analyzes (glucose, nitrogen, blood count,

lipids, etc.), liver function tests: alanine aminotransferase

(ALT), albumin, PT, PTT etc., and ultrasonography findings

of the upper abdomen, were performed. For differential diagnosis

of chronic or other liver diseases (hereditary metabolic

diseases, autoimmune hepatitis, liver cancer, etc.), selected

tests (ceruloplasmin, alpha 1 antitripsin, autoantibodies etc.),

and tumor markers (AFP and CEA), were done. Patients suspected

for liver or other malignancy were excluded from the

study. Serological tests for HBV, HCV, and HIV markers were

done by third generation enzyme-linked immunosorbent

assay (ELISA) with commercial kits. Positive anti HCV sera

was confirmed using recombinant immunoblot assay

(RIBA).

Statistical analysis was done for parametric and non-parametric

data (Student's t test, x2 test). A p<0.05 was considered

significant.

RESULTS

1. Aetiology of chronic liver disease

The etiology of chronic liver disease is shown in Figure 1.

The majority of 212 studied patients had chronic viral

hepatitis (84%) (DF=5; x2 =300.2;p<0.01).

Autoimmune hepatitis, alcoholic liver disease and nonalcoholic

liver steatosis/steatohepatitis (mainly caused by

type II diabetes mellitus and hypelipidemia), were other discovered

diseases, but in a significant lower number of

patients. Liver steatosis or steatohepatitis were defined by

ultrasonography finding of fatty liver depending on presence

of ALT elevation.

2. Aetiology of chronic viral hepatitis

Among of 179 patients with chronic viral hepatitis, mostly

(122/179; 68%) of them had HCV infection. A significant

lower number (56/179; 31%) of patients had chronic B

hepatitis (DF=5; x2 =300.1;p<0.01).

One patient had dual infection with both viruses.

3. Gender of patients with chronic viral hepatitis

The overall prevalence of male gender in total number

of patients with chronic viral hepatitis was significantly

higher in males: 64% than females: 36%

DF=1;x2=0.11;p<0.05).

Prevalence of male gender was also significantly higher

in each group of patients with CH-C (DF=1; x2=8.5;

p<0.01), and CH-B (DF=1; x2=5.8;p<0.05).

4. Age of patients with chronic viral hepatitis

Age distribution by etiology in patients with chronic

viral hepatitis is shown in Figure 2.

Mean age of patients with chronic viral hepatitis was 38

years (8=38.6;SD=14.8). Group of patients aged from 21-

30 years was most frequent (DF=6; x2=87.8;p<0.01). Age

of patients with CH-C were from 13-76 years (8C=35.8;

SD=15.7), while patients with CH-B were aged from 17-71

years (8B=41.5;SD=12.9).

Analyzing age by etiology of CVH, significant difference

was noticed between patients with CH-C and CH-B;

patients with CH-C were significantly younger than

patients with CH-B (DF=6; x2 =33.3;p<0.01).

Group of patients aged from 21-30 years was the most

frequent in CH-C, while in CH-B, the most frequent group

included patients from 41-50 years

(DFC=6; x2=94.5;p<0.01; DFB=6; x2=41;p<0.01).

5. Epidemiological data of patients

a. The overall prevalence of positive (73/122) and negative

(49/122) epidemiological data was similar in CH-C

patients (DF=1; x2 =4;p>0.05). In contrast, the majority of

patients (13/56) with CH-B had no epidemiological data of

infection (DF=14; x2=14;p< 0.01).

Patient with dual HCV and HBV infection had no data

about its risk.

b. Patients with positive epidemiologal data were further

analyzed in details about the route of infection and the

results are shown in Table 1., and Table 2.

The majority of patients with CH-C had history data

about i.v. drug use (80%) (DF=5; x2 =198.8;p<0.01). In

total number of patients with CH-C, i.v. drug users were

48.36%.

Seven out of 73 patients received blood transfusion,

other routes of infection were less found.

Among patients with CH-B, 5/13 were infected by accidental

injury. All patients were healthcare workers, three of

them were dentists. Household contacts with infected person

were noticed in three patients.

6. Co-morbidity of chronic viral hepatitis with other

diseases

Investigations of patients history, clinical and biochemical

data, and ultrasonography findings, revealed other diseases

shown in Table 3., and Table 4.

The most common finding of associated disease in

patients with CH-C was unknown caused liver

steatosis/steatohepatitis (10/16, or 8% of total patients

with CH-C) (DF=3; x2=2.77;p>0.05).

Steatosis/steatohepatitis of unknown cause was also the

most frequent finding in patients with CH-B (7/11 or 12%

of total patients with CH-B).

7. Values of alanine aminotransferase in patients with

chronic viral hepatitis

Values of alanine aminotransfere were divided in 5

groups: normal value, up to 2.5x, from 2.5-5x, from 5-10x,

and 10x upper limit than normal value, respectively.

The results of ALT values are shown in Figure 3.

8. Viral hepatitis

Mild elevation of ALT values (from normal-2.5x upper

limit of normal value), were noticed significantly most frequent

in total number of patients (45.28%)

(DF=5; x2=21.7;p<0.01).

As well, mild elevation of ALT values was most frequent

in the majority in each group of patients (CH-C:

DF=4; x2 =5.8; p<0.01) (CH-B: DF=4; x2=45.8;p<0.01).

Comparing etiology and ALT values, significant higher

values of ALT were noticed in patients with CH-C then in

CH-B patients (DF=5; x2 =16.7; p<0.01).

Persistently normal ALT values were defined by at least

3 determinations within screening period of 6 months or

longer. Normal values of ALT were found in 17/115

(14.78%%), and 22/53 (41.51%) in CH-C and CH-B

patients, respectively. In CH-C patients, younger aged

group (from 20-31 years) was sifnificantly higher than

other groups. (DF=5; x2=20.7;p<0.01). In this group of

patients, CH-C patients, there was no difference between

gender (DF=9; x2 =0;p>0.05).

In CH-C patients with normal ALT values, positive

antibodies to HCV confirmed the diagnosis. HCV RNA

was not determined. In CH-B patients, HBeAg was done in

6/22 patients, and was negative.

Analyzed ALT values in CH-C patients with associated

other diseases did not show any significant difference

(DF=3; x2=2.77;p>0.05).

9. Clinical features of patients with chronic viral

hepatitis

Evaluation of clinical, biochemical and ultrasonography

findings of patients with chronic viral hepatitis confirmed

that mostly of them had chronic hepatitis without

liver cirrhosis (CH-C: 94%, CH-B: 93%).

DISCUSSION

Chronic liver disease has different aspects. Patients

usually have no symptoms until liver cirrhosis and its complications

developed. Elevated aminotransferase values,

often at routine laboratory examination, usually take them

to hepatology units for evaluating possible liver disease.

One of the most important assignments for hepatologist is

to make correct differential diagnosis in order to recognize

disease, cure it with adequate therapy, and prevent its serious

outcome. Moreover, particular problem in outpatients

were wide spectrum of laboratory testings, careful clinical

examination, detailed history taking and epidemiological

data, and if necessary, additional radiological imaging that

must be done.

Our study was conducted in Hepatology Clinic which

prime purpose is in diagnosing and following-up patients

with infectious diseases. Exclusion or confirmation viral

aetiology in the spectrum of other chronic liver disease is

the first step for many general practitioners or gastroenterologists.

From diverse laboratories, blood transfusion

units, hemodialysis centers and phsyhiatric departments,

patients with positive hepatitis viruses are directed to visit

our Clinic for further clinical examination. Because of that,

the results of our investigation in two-year period strengthened

the fact that majority of outpatients (84%) have

chronic viral hepatitis, exclusively caused by HCV and

HBV. Our study discovers more number of patients with

chronic HCV infection (84%) than CH-B, which is also,

general epidemiological trend in other countries in the last

decade (1). Because of the similar transmission route, it

was expected a possible co-infection with both viruses and

we noticed it, but only in one patient.

This investigation confirms that males (64%) suffer

from CVH more than females, independently on aetiology.

Past data from the literature and our experience that persistence

of HBV is more often in males, are not completely

resolved until now. Some incomplete explanation was

given through interfering of hormones and viral replication.

Recently published epidemiological studies of HCV

also confirmed more inclination of males to become long

term carriers, after discovering that young females could

eradicate the virus up to 50% (23). At the same time, in our

socioeconomic milieu, males are more liable for behavioral

risks such as drug abuse and promiscuity what is critical

for percutaneous and sexual infection with both viruses.

Intravenous drug use has replaced blood transfusion as

the most common route of transmission of HCV.

Approximately 90% of drug users after 5 years become

infected (24,25). Such drug use accounts for around two

thirds of HCV infections in U.S., and other developed

countries. As it was expected in our study, in CH-C, more

frequent patients were males, younger age (from 20-31

years) and drug users (49%). On the contrary, majorities of

patients with CH-B had no data about infection and were

older than CH-C patients. Drug abuse as an epidemiological

risk is confirmed only in 15% of these patients.

Interesting data is that only one patient with CH-C (lower

than 1% of total patients), was infected through hemodialysis.

According to data from several dialysis departments

in our country, almost 80% patients are infected with HCV

(Dr. S. Zerjav, personal communication).

It is worth to stress that among CH-B patients, 8/56

(14%) were infected through accidental injury or household

contacts. This data requires use of preventive vaccination

measures of all healthcare workers and persons living

with infected patients, including sexual partners and

other relatives (26,27).

The specific factors that lead to progression of CVH are

still unclear. Investigation of associated diseases in our

patients discovered few patients with chronic consummation

of alcohol, type II diabetes mellitus and body overweight.

But, most frequent finding in our study was

unknown caused fatty liver estimated by ultrasonography.

It is almost equally presented in CH-C and CH-B (8% and

12%, respectively), although that is more typical for CH-C

(28,29). It is notified that steatosis in CH-C can be conspicuous

in up to 60% by liver biopsy, induced by metabolic

disturbances, mainly diabetes mellitus type II and

obesity. Virus itself can be also a cause for fatty infiltration,

particularly in genotype 3, when its core and nonstructural

part of the genome (NS5A), disrupt intracellular uptake

and transport of lipids. However, only ultrasonography

examination is not complete for evaluation of fatty infiltration,

especially because of the fact that liver fibrosis can be

expressed as liver steatosis. Liver biopsy, what was not

done in our patients, certainly would be better to estimate

and differentiate this finding.

Clinically, CHV characterizes the insidious nature of

the disease and ALT values may be normal or fluctuate

over its course. Generally, mainly of patients have mild

elevation of ALT as it was noticed in our study (45%). In

HCV infection, extremely high values of ALT (more than

5-10 x upper limit of normal), can be found rarely, does not

correlate with disease progression or viral replication, even

in an acute hepatitis (20-22). During the course of CH-B,

after several years of infection, HBe antigen seroconversion

is followed with high elevation of ALT values in

approximately one third of patients. After that e.g. "elimination"

phase, the later course of the disease is relative

benign and is defined as "inactive". (30,31). "Inactive" disease

could explain lower activity of ALT values in CH-B,

especially, because of older age of patients. Another possibility

could be a high prevalence of drug users in CH-C in

our study, and combined toxic and viral effects on liver

necrosis. In addition, active drug use could explain that

lower prevalence of normal ALT values (14%), what was

found in other studies (approximately 30 %). Otherwise,

normal ALT values are found mostly in younger patients

(aged from 21-30 years), and without difference in gender.

That is in contrast to literature data that population with

normal ALT has distinct features, with inverted male to

female ratio and with no difference in age (32,33). As we

had not possibility to detect HCV RNA in outpatients, it is

difficult to differentiate if positive anti HCV antibodies in

these patients means present or, eventually past infection

(34). As well, in CH-B patients with normal ALT values,

we confirmed negativity of HBe antigen in 6/22 patients.

Comparing ALT values in CH-C patients associated

with other diseases that can accelerate progression of the

disease, we did not find a significant difference, and can

not conclude that this laboratory parameter, without

histopatological finding could be a "surrogate" markers for

liver necrosis and consecutive fibrosis (35-37).

The result that clinical feature of our patients was mainly

without cirrhosis (more than 90%), is explained by the

fact that patients with end stage of liver disease usually

need an intensive hospital care. Possible serious complications

not allowed these patients to be followed-up in the

Clinic for a long period.

In conclusion, the outpatients with chronic hepatitis in

Hepatology Clinic characterized viral infection, mainly

with HCV, and mild clinical features. High-risk populations

are young males, particularly drug users. Beside biochemical,

clinical and radiological imagining data,

histopathological examination is necessary for complete

evaluation of the disease. It can estimate possible associated

disease and stage of fibrosis that is most competent factor

for evaluation of disease progression.

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