Clinical, Biochemical and Imaging-Verified Regression of Hepatitis B-Induced Cirrhosis

[Guest guest]

From Liver International

Clinical, Biochemical and Imaging-Verified Regression of Hepatitis B-Induced

Cirrhosis

Posted 06/02/2004

1Department of Gastroenterology and 2Department of Pathology, Shariati

Hospital, Digestive Diseases Research Center, Tehran University of Medical

Sciences, Tehran, Iran

S. Massarrat; V. Fallahazad; N. Kamalian

Abstract and Introduction

Abstract

In a 65-year-old patient with ascites, jaundice and positive hepatitis B

surface antigen (HBsAg), the histological diagnosis of cirrhosis with

knodell total score 13 was made in 1995. The patient was followed up for 8

years. Spontaneous seroconversion of HBsAg appeared. Except for slight

hyperbilirubinemia, all pathologic, clinical laboratory data remained normal

from the second year of diagnosis till 8 years of follow-up. In the last

follow up, the markers of liver fibrosis were all normal. The portal vein

diameter was decreased and the esophageal varices disappeared. The imaging

of liver by sonography and CT-scan did not reveal any abnormality.

Introduction

Cirrhosis is a diffuse transformation and disorganization of the liver

parenchyma with disturbance of the spatial relationships between portal

tracts and hepatic veins and nodule formation by extensive fibrosis. This

stage of liver disease is considered to be irreversible and the death of

patients due to the complications is unavoidable. There are few reports

about the regression of cirrhosis and resolution of the advanced liver

disease.

We report here about the regression of hepatitis B-induced cirrhosis in a

patient after being followed over 8 years.

Case Report

A 65-year-old patient with a history of diabetes since 16 years treated with

insulin had no problems up to 2.5 months before presenting to us. He got

then jaundice accompanied by general weakness, fever, nausea and vomiting.

After few weeks he felt better, but his abdomen became distended and got

peripheral edema, which is slightly improved by absolute rest. By CT-scan,

small liver with some ascites was verified. By upper gastrointestinal (GI)

endoscopy, grade II esophageal varices were detected. The patient was

admitted in June 1995 in our hospital for diagnosis and treatment of

jaundice and ascites.

By clinical examination, he had jaundice, some distended abdomen and

peripheral edema. He had palmar erythema, no spider angioma was noted. The

liver and spleen were not palpable. His weight was 60 kg.

Following laboratory data were registered: sedimentation rate 20/1 h, Hb

12.3 g/dl, WBC 7000 cells/mm2, hematocrit 35.7%, MCV 88.4 fl, platelet count

110,000/mm2.

Blood sugar 111 mg%, cholesterol 148 mg%, HBsAg positive, hepatitis e

antigen (HBeAg) negative, hepatitis B core antigen (HBcAb) positive. The

results of liver function test are given in Table 1.

By ultrasound exam, the liver was not enlarged, rather small. The

echogenicity was increased. The gallbladder was distended and contained

sludges. Ascites was present. By two times paracentesis 7 l fluid was

removed. Therapy was started with furosemide 40 mg and spironolactone 75 mg

daily. Protein concentration in ascitic fluid was 185 mg% and WBC 50/mm2.

Two weeks after the admission, under i.v. injection of 2 U frozen plasma, a

liver biopsy was taken.

Histologic Finding

Portal areas are enlarged distended to the surrounding lobules, form

portoportal bridges and pseudolobules. Regenerative nodule are present (Fig.

1). Inflammatory mononuclear cells are distended to the marginal plates.

This distention is seen in all zones of parenchymatous lobule and

pseudolobules, rosette formation and piecemeal necrosis are present. The

hepatocytes are swollen; contain ballooning degeneration with marked

deposition of bile in the cytoplasm, bile plugs are noted in bile

canaliculi. The reticuloendothelial cells are proliferated. By special

staining collagen deposits are detected markedly in the portal tracts. The

reticulin is heavily deposited in the sinusoidal walls and in the portal

areas so that the lobular and trabecular pattern are destroyed (Fig. 2).

Immunohistochemical staining for B-virus particles revealed heavy

accumulation in the hepatocytes (Fig. 3). Knodell scoring revealed stage 3-4

and grade 10 (total score was 13-14).

The patient was followed in irregular yearly intervals. He was treated with

Propranolol 40 mg, Spirinolactone 50 mg daily and insulin for his diabetes.

One year later, he had no ascites and jaundice. Two years later and in the

following years all liver function tests were normal except an

hyperbilirubinemia with predominant indirect bilirubin (Table 1).

Abdominal sonography in May 1998 revealed nonenlarged liver with homogenous

structure and increased echogenicity. The anterioposterior angle of the left

lobe was enlarged. The diameter of portal vein with 14 mm was increased. The

spleen had a normal size with a length of 9.7 cm and width of 5.5 cm (Fig.

4). In September 2000, the ultrasound of abdomen showed normal size of liver

by no increased echogenicity. The diameter of portal vein with 11 mm was

normal. The last abdominal sonography in June 2002 revealed normal size of

liver with a homogenous structure and smooth liver surface, and the diameter

of portal vein was 11 mm (Fig. 4B). The CT scan of the liver and spleen

confirmed the sonographic finding with normal size and smooth surface of

liver (Fig. 5). By the last follow-up examination (August 2003) upper GI

endoscopy revealed disappearance of esophageal varices (Fig. 6a, . Severe

antral gastritis with yellow and red patchy areas without hypertensive

gastropathy was verified. The markers of liver fibrosis were determined[1]:

Haptoglobin with 0.66 g/l (normal 0.3-1.53 g/l), Apolipoprotein A1 with 198

mg% (normal 110-200 mg%), ?-Glutamyl transpeptidase with 10 U/l (normal up

to 40 U/l) and ?-globulin with 15.1% (normal </=18%) were all normal.

Discussion

Cirrhosis is an end-stage process of chronic progressive scarring

inflammation caused mainly by viral hepatitis B and C as well as alcohol.

Once cirrhosis established, it has been considered to be irreversible. When

complications of cirrhosis like ascites, severe encephalopathy, jaundice

with variceal bleeding developed, the survival of cirrhotic patients becomes

short and lethality is unavoidable.

Research in the last decade has shown that hepatic fibrosis is a dynamic

process involving deposition and degradation of fibrillar collagens and

other extracellular matrix proteins.[2] Degradation of matrix proteins

occurs by interstitial collagenase regulated by specific molecules called

tissue inhibitors of metalloproteases produced by hepatic stellate

cells.[3-5] The reversibility of hepatic fibrosis seems to be probable and

intensive effort is being made on compounds with antifibrotic agents. The

point at which cirrhosis or extensive fibrosis becomes irreversible, has not

been well-defined.

There are few reports with regard to regression of cirrhosis by intensive

treatment; some patients with autoimmune hepatitis and cirrhosis treated

with immunosuppressive medications responded with regression of

fibrosis.[6,7] Reversal of fibrosis after treatment of hemochromatosis with

phlebotomies was observed in the earlier decades.[8,9] 's disease

after treatment with penicillamine showed normalization of liver

morphology.[10] Regression of fibrosis and cirrhosis were observed in

secondary biliary cirrhosis after biliary decompression,[11,12] and in

primary biliary cirrhosis after treatment.[13]

The regression of cirrhosis is not limited only to cirrhosis with nonviral

etiology. In an hepatology-oriented clinic in Germany, Müting and coworkers

observed regression of cirrhosis in eight of 100 patients with cirrhosis of

different aetiology over a period of 20 years.[14] Resolution of B- and

D-induced cirrhosis over 12 years under interferon therapy[15] and

regression of decompensated liver cirrhosis resulting from B-hepatitis under

lamivudin were the most recent examples.[16] Reversibility of advanced stage

of hepatitis C-induced cirrhosis under combination therapy with pegylated

interferon a-2b and ribavirin is observed, when hepatitis C viremia

cleared.[17]

The course of liver disease in our case shows the regression of cirrhosis

and portal hypertension verified 8 years ago on the base of clinical,

biochemical and abdominal imaging. A liver biopsy specimen taken blindly

from one lobe of liver can give in 21% a false negative result when compared

with laparoscopically obtainable specimens taken under direct view.[18,19]

Therefore, we could only be sure of exact diagnosis, when we were able to

perform laparoscopy to verify the macroscopic and histological regression of

cirrhosis, which was not ethically justified in our patient. The imaging

technique by abdominal ultrasound revealed a regression of increased

echogenicity and decrease of diameter of portal vein. The CT-scan could not

detect any abnormal finding in favor of chronic liver disease.

The regression of cirrhosis and portal hypertension in our patient occurred

by seroconversion of hepatitis B virus by lack of HBeAg without any

therapeutic intervention. We did not measure the titer of HBV-DNA at that

time. Spontaneous clearance of viremia in patients with chronic HBV

infection occurs in 0.4-2% per year in white patients and 0.1-0.8% per year

in Chinese patients.[20] This probably T cell transmitted enhancement of

immune response resulted in clearance of viremia and inducing remission and

regression of chronic hepatitis and cirrhosis caused by HB-[21] HC- viral

infection.[22]

From the animal models and some case reports, as well as from the recent

clinical studies, the old opinion about the traditional view of cirrhosis as

a progressive irreversible disease is no longer correct. We must accept the

new view of reversal of fibrosis and cirrhosis, when the underlying cause

can be removed and the process of fibrogenesis is stopped by antifibrotic

agents.

http://www.medscape.com/viewarticle/474566_1

[Guest guest]

From Liver International

Clinical, Biochemical and Imaging-Verified Regression of Hepatitis B-Induced

Cirrhosis

Posted 06/02/2004

1Department of Gastroenterology and 2Department of Pathology, Shariati

Hospital, Digestive Diseases Research Center, Tehran University of Medical

Sciences, Tehran, Iran

S. Massarrat; V. Fallahazad; N. Kamalian

Abstract and Introduction

Abstract

In a 65-year-old patient with ascites, jaundice and positive hepatitis B

surface antigen (HBsAg), the histological diagnosis of cirrhosis with

knodell total score 13 was made in 1995. The patient was followed up for 8

years. Spontaneous seroconversion of HBsAg appeared. Except for slight

hyperbilirubinemia, all pathologic, clinical laboratory data remained normal

from the second year of diagnosis till 8 years of follow-up. In the last

follow up, the markers of liver fibrosis were all normal. The portal vein

diameter was decreased and the esophageal varices disappeared. The imaging

of liver by sonography and CT-scan did not reveal any abnormality.

Introduction

Cirrhosis is a diffuse transformation and disorganization of the liver

parenchyma with disturbance of the spatial relationships between portal

tracts and hepatic veins and nodule formation by extensive fibrosis. This

stage of liver disease is considered to be irreversible and the death of

patients due to the complications is unavoidable. There are few reports

about the regression of cirrhosis and resolution of the advanced liver

disease.

We report here about the regression of hepatitis B-induced cirrhosis in a

patient after being followed over 8 years.

Case Report

A 65-year-old patient with a history of diabetes since 16 years treated with

insulin had no problems up to 2.5 months before presenting to us. He got

then jaundice accompanied by general weakness, fever, nausea and vomiting.

After few weeks he felt better, but his abdomen became distended and got

peripheral edema, which is slightly improved by absolute rest. By CT-scan,

small liver with some ascites was verified. By upper gastrointestinal (GI)

endoscopy, grade II esophageal varices were detected. The patient was

admitted in June 1995 in our hospital for diagnosis and treatment of

jaundice and ascites.

By clinical examination, he had jaundice, some distended abdomen and

peripheral edema. He had palmar erythema, no spider angioma was noted. The

liver and spleen were not palpable. His weight was 60 kg.

Following laboratory data were registered: sedimentation rate 20/1 h, Hb

12.3 g/dl, WBC 7000 cells/mm2, hematocrit 35.7%, MCV 88.4 fl, platelet count

110,000/mm2.

Blood sugar 111 mg%, cholesterol 148 mg%, HBsAg positive, hepatitis e

antigen (HBeAg) negative, hepatitis B core antigen (HBcAb) positive. The

results of liver function test are given in Table 1.

By ultrasound exam, the liver was not enlarged, rather small. The

echogenicity was increased. The gallbladder was distended and contained

sludges. Ascites was present. By two times paracentesis 7 l fluid was

removed. Therapy was started with furosemide 40 mg and spironolactone 75 mg

daily. Protein concentration in ascitic fluid was 185 mg% and WBC 50/mm2.

Two weeks after the admission, under i.v. injection of 2 U frozen plasma, a

liver biopsy was taken.

Histologic Finding

Portal areas are enlarged distended to the surrounding lobules, form

portoportal bridges and pseudolobules. Regenerative nodule are present (Fig.

1). Inflammatory mononuclear cells are distended to the marginal plates.

This distention is seen in all zones of parenchymatous lobule and

pseudolobules, rosette formation and piecemeal necrosis are present. The

hepatocytes are swollen; contain ballooning degeneration with marked

deposition of bile in the cytoplasm, bile plugs are noted in bile

canaliculi. The reticuloendothelial cells are proliferated. By special

staining collagen deposits are detected markedly in the portal tracts. The

reticulin is heavily deposited in the sinusoidal walls and in the portal

areas so that the lobular and trabecular pattern are destroyed (Fig. 2).

Immunohistochemical staining for B-virus particles revealed heavy

accumulation in the hepatocytes (Fig. 3). Knodell scoring revealed stage 3-4

and grade 10 (total score was 13-14).

The patient was followed in irregular yearly intervals. He was treated with

Propranolol 40 mg, Spirinolactone 50 mg daily and insulin for his diabetes.

One year later, he had no ascites and jaundice. Two years later and in the

following years all liver function tests were normal except an

hyperbilirubinemia with predominant indirect bilirubin (Table 1).

Abdominal sonography in May 1998 revealed nonenlarged liver with homogenous

structure and increased echogenicity. The anterioposterior angle of the left

lobe was enlarged. The diameter of portal vein with 14 mm was increased. The

spleen had a normal size with a length of 9.7 cm and width of 5.5 cm (Fig.

4). In September 2000, the ultrasound of abdomen showed normal size of liver

by no increased echogenicity. The diameter of portal vein with 11 mm was

normal. The last abdominal sonography in June 2002 revealed normal size of

liver with a homogenous structure and smooth liver surface, and the diameter

of portal vein was 11 mm (Fig. 4B). The CT scan of the liver and spleen

confirmed the sonographic finding with normal size and smooth surface of

liver (Fig. 5). By the last follow-up examination (August 2003) upper GI

endoscopy revealed disappearance of esophageal varices (Fig. 6a, . Severe

antral gastritis with yellow and red patchy areas without hypertensive

gastropathy was verified. The markers of liver fibrosis were determined[1]:

Haptoglobin with 0.66 g/l (normal 0.3-1.53 g/l), Apolipoprotein A1 with 198

mg% (normal 110-200 mg%), ?-Glutamyl transpeptidase with 10 U/l (normal up

to 40 U/l) and ?-globulin with 15.1% (normal </=18%) were all normal.

Discussion

Cirrhosis is an end-stage process of chronic progressive scarring

inflammation caused mainly by viral hepatitis B and C as well as alcohol.

Once cirrhosis established, it has been considered to be irreversible. When

complications of cirrhosis like ascites, severe encephalopathy, jaundice

with variceal bleeding developed, the survival of cirrhotic patients becomes

short and lethality is unavoidable.

Research in the last decade has shown that hepatic fibrosis is a dynamic

process involving deposition and degradation of fibrillar collagens and

other extracellular matrix proteins.[2] Degradation of matrix proteins

occurs by interstitial collagenase regulated by specific molecules called

tissue inhibitors of metalloproteases produced by hepatic stellate

cells.[3-5] The reversibility of hepatic fibrosis seems to be probable and

intensive effort is being made on compounds with antifibrotic agents. The

point at which cirrhosis or extensive fibrosis becomes irreversible, has not

been well-defined.

There are few reports with regard to regression of cirrhosis by intensive

treatment; some patients with autoimmune hepatitis and cirrhosis treated

with immunosuppressive medications responded with regression of

fibrosis.[6,7] Reversal of fibrosis after treatment of hemochromatosis with

phlebotomies was observed in the earlier decades.[8,9] 's disease

after treatment with penicillamine showed normalization of liver

morphology.[10] Regression of fibrosis and cirrhosis were observed in

secondary biliary cirrhosis after biliary decompression,[11,12] and in

primary biliary cirrhosis after treatment.[13]

The regression of cirrhosis is not limited only to cirrhosis with nonviral

etiology. In an hepatology-oriented clinic in Germany, Müting and coworkers

observed regression of cirrhosis in eight of 100 patients with cirrhosis of

different aetiology over a period of 20 years.[14] Resolution of B- and

D-induced cirrhosis over 12 years under interferon therapy[15] and

regression of decompensated liver cirrhosis resulting from B-hepatitis under

lamivudin were the most recent examples.[16] Reversibility of advanced stage

of hepatitis C-induced cirrhosis under combination therapy with pegylated

interferon a-2b and ribavirin is observed, when hepatitis C viremia

cleared.[17]

The course of liver disease in our case shows the regression of cirrhosis

and portal hypertension verified 8 years ago on the base of clinical,

biochemical and abdominal imaging. A liver biopsy specimen taken blindly

from one lobe of liver can give in 21% a false negative result when compared

with laparoscopically obtainable specimens taken under direct view.[18,19]

Therefore, we could only be sure of exact diagnosis, when we were able to

perform laparoscopy to verify the macroscopic and histological regression of

cirrhosis, which was not ethically justified in our patient. The imaging

technique by abdominal ultrasound revealed a regression of increased

echogenicity and decrease of diameter of portal vein. The CT-scan could not

detect any abnormal finding in favor of chronic liver disease.

The regression of cirrhosis and portal hypertension in our patient occurred

by seroconversion of hepatitis B virus by lack of HBeAg without any

therapeutic intervention. We did not measure the titer of HBV-DNA at that

time. Spontaneous clearance of viremia in patients with chronic HBV

infection occurs in 0.4-2% per year in white patients and 0.1-0.8% per year

in Chinese patients.[20] This probably T cell transmitted enhancement of

immune response resulted in clearance of viremia and inducing remission and

regression of chronic hepatitis and cirrhosis caused by HB-[21] HC- viral

infection.[22]

From the animal models and some case reports, as well as from the recent

clinical studies, the old opinion about the traditional view of cirrhosis as

a progressive irreversible disease is no longer correct. We must accept the

new view of reversal of fibrosis and cirrhosis, when the underlying cause

can be removed and the process of fibrogenesis is stopped by antifibrotic

agents.

http://www.medscape.com/viewarticle/474566_1

[Guest guest]

From Liver International

Clinical, Biochemical and Imaging-Verified Regression of Hepatitis B-Induced

Cirrhosis

Posted 06/02/2004

1Department of Gastroenterology and 2Department of Pathology, Shariati

Hospital, Digestive Diseases Research Center, Tehran University of Medical

Sciences, Tehran, Iran

S. Massarrat; V. Fallahazad; N. Kamalian

Abstract and Introduction

Abstract

In a 65-year-old patient with ascites, jaundice and positive hepatitis B

surface antigen (HBsAg), the histological diagnosis of cirrhosis with

knodell total score 13 was made in 1995. The patient was followed up for 8

years. Spontaneous seroconversion of HBsAg appeared. Except for slight

hyperbilirubinemia, all pathologic, clinical laboratory data remained normal

from the second year of diagnosis till 8 years of follow-up. In the last

follow up, the markers of liver fibrosis were all normal. The portal vein

diameter was decreased and the esophageal varices disappeared. The imaging

of liver by sonography and CT-scan did not reveal any abnormality.

Introduction

Cirrhosis is a diffuse transformation and disorganization of the liver

parenchyma with disturbance of the spatial relationships between portal

tracts and hepatic veins and nodule formation by extensive fibrosis. This

stage of liver disease is considered to be irreversible and the death of

patients due to the complications is unavoidable. There are few reports

about the regression of cirrhosis and resolution of the advanced liver

disease.

We report here about the regression of hepatitis B-induced cirrhosis in a

patient after being followed over 8 years.

Case Report

A 65-year-old patient with a history of diabetes since 16 years treated with

insulin had no problems up to 2.5 months before presenting to us. He got

then jaundice accompanied by general weakness, fever, nausea and vomiting.

After few weeks he felt better, but his abdomen became distended and got

peripheral edema, which is slightly improved by absolute rest. By CT-scan,

small liver with some ascites was verified. By upper gastrointestinal (GI)

endoscopy, grade II esophageal varices were detected. The patient was

admitted in June 1995 in our hospital for diagnosis and treatment of

jaundice and ascites.

By clinical examination, he had jaundice, some distended abdomen and

peripheral edema. He had palmar erythema, no spider angioma was noted. The

liver and spleen were not palpable. His weight was 60 kg.

Following laboratory data were registered: sedimentation rate 20/1 h, Hb

12.3 g/dl, WBC 7000 cells/mm2, hematocrit 35.7%, MCV 88.4 fl, platelet count

110,000/mm2.

Blood sugar 111 mg%, cholesterol 148 mg%, HBsAg positive, hepatitis e

antigen (HBeAg) negative, hepatitis B core antigen (HBcAb) positive. The

results of liver function test are given in Table 1.

By ultrasound exam, the liver was not enlarged, rather small. The

echogenicity was increased. The gallbladder was distended and contained

sludges. Ascites was present. By two times paracentesis 7 l fluid was

removed. Therapy was started with furosemide 40 mg and spironolactone 75 mg

daily. Protein concentration in ascitic fluid was 185 mg% and WBC 50/mm2.

Two weeks after the admission, under i.v. injection of 2 U frozen plasma, a

liver biopsy was taken.

Histologic Finding

Portal areas are enlarged distended to the surrounding lobules, form

portoportal bridges and pseudolobules. Regenerative nodule are present (Fig.

1). Inflammatory mononuclear cells are distended to the marginal plates.

This distention is seen in all zones of parenchymatous lobule and

pseudolobules, rosette formation and piecemeal necrosis are present. The

hepatocytes are swollen; contain ballooning degeneration with marked

deposition of bile in the cytoplasm, bile plugs are noted in bile

canaliculi. The reticuloendothelial cells are proliferated. By special

staining collagen deposits are detected markedly in the portal tracts. The

reticulin is heavily deposited in the sinusoidal walls and in the portal

areas so that the lobular and trabecular pattern are destroyed (Fig. 2).

Immunohistochemical staining for B-virus particles revealed heavy

accumulation in the hepatocytes (Fig. 3). Knodell scoring revealed stage 3-4

and grade 10 (total score was 13-14).

The patient was followed in irregular yearly intervals. He was treated with

Propranolol 40 mg, Spirinolactone 50 mg daily and insulin for his diabetes.

One year later, he had no ascites and jaundice. Two years later and in the

following years all liver function tests were normal except an

hyperbilirubinemia with predominant indirect bilirubin (Table 1).

Abdominal sonography in May 1998 revealed nonenlarged liver with homogenous

structure and increased echogenicity. The anterioposterior angle of the left

lobe was enlarged. The diameter of portal vein with 14 mm was increased. The

spleen had a normal size with a length of 9.7 cm and width of 5.5 cm (Fig.

4). In September 2000, the ultrasound of abdomen showed normal size of liver

by no increased echogenicity. The diameter of portal vein with 11 mm was

normal. The last abdominal sonography in June 2002 revealed normal size of

liver with a homogenous structure and smooth liver surface, and the diameter

of portal vein was 11 mm (Fig. 4B). The CT scan of the liver and spleen

confirmed the sonographic finding with normal size and smooth surface of

liver (Fig. 5). By the last follow-up examination (August 2003) upper GI

endoscopy revealed disappearance of esophageal varices (Fig. 6a, . Severe

antral gastritis with yellow and red patchy areas without hypertensive

gastropathy was verified. The markers of liver fibrosis were determined[1]:

Haptoglobin with 0.66 g/l (normal 0.3-1.53 g/l), Apolipoprotein A1 with 198

mg% (normal 110-200 mg%), ?-Glutamyl transpeptidase with 10 U/l (normal up

to 40 U/l) and ?-globulin with 15.1% (normal </=18%) were all normal.

Discussion

Cirrhosis is an end-stage process of chronic progressive scarring

inflammation caused mainly by viral hepatitis B and C as well as alcohol.

Once cirrhosis established, it has been considered to be irreversible. When

complications of cirrhosis like ascites, severe encephalopathy, jaundice

with variceal bleeding developed, the survival of cirrhotic patients becomes

short and lethality is unavoidable.

Research in the last decade has shown that hepatic fibrosis is a dynamic

process involving deposition and degradation of fibrillar collagens and

other extracellular matrix proteins.[2] Degradation of matrix proteins

occurs by interstitial collagenase regulated by specific molecules called

tissue inhibitors of metalloproteases produced by hepatic stellate

cells.[3-5] The reversibility of hepatic fibrosis seems to be probable and

intensive effort is being made on compounds with antifibrotic agents. The

point at which cirrhosis or extensive fibrosis becomes irreversible, has not

been well-defined.

There are few reports with regard to regression of cirrhosis by intensive

treatment; some patients with autoimmune hepatitis and cirrhosis treated

with immunosuppressive medications responded with regression of

fibrosis.[6,7] Reversal of fibrosis after treatment of hemochromatosis with

phlebotomies was observed in the earlier decades.[8,9] 's disease

after treatment with penicillamine showed normalization of liver

morphology.[10] Regression of fibrosis and cirrhosis were observed in

secondary biliary cirrhosis after biliary decompression,[11,12] and in

primary biliary cirrhosis after treatment.[13]

The regression of cirrhosis is not limited only to cirrhosis with nonviral

etiology. In an hepatology-oriented clinic in Germany, Müting and coworkers

observed regression of cirrhosis in eight of 100 patients with cirrhosis of

different aetiology over a period of 20 years.[14] Resolution of B- and

D-induced cirrhosis over 12 years under interferon therapy[15] and

regression of decompensated liver cirrhosis resulting from B-hepatitis under

lamivudin were the most recent examples.[16] Reversibility of advanced stage

of hepatitis C-induced cirrhosis under combination therapy with pegylated

interferon a-2b and ribavirin is observed, when hepatitis C viremia

cleared.[17]

The course of liver disease in our case shows the regression of cirrhosis

and portal hypertension verified 8 years ago on the base of clinical,

biochemical and abdominal imaging. A liver biopsy specimen taken blindly

from one lobe of liver can give in 21% a false negative result when compared

with laparoscopically obtainable specimens taken under direct view.[18,19]

Therefore, we could only be sure of exact diagnosis, when we were able to

perform laparoscopy to verify the macroscopic and histological regression of

cirrhosis, which was not ethically justified in our patient. The imaging

technique by abdominal ultrasound revealed a regression of increased

echogenicity and decrease of diameter of portal vein. The CT-scan could not

detect any abnormal finding in favor of chronic liver disease.

The regression of cirrhosis and portal hypertension in our patient occurred

by seroconversion of hepatitis B virus by lack of HBeAg without any

therapeutic intervention. We did not measure the titer of HBV-DNA at that

time. Spontaneous clearance of viremia in patients with chronic HBV

infection occurs in 0.4-2% per year in white patients and 0.1-0.8% per year

in Chinese patients.[20] This probably T cell transmitted enhancement of

immune response resulted in clearance of viremia and inducing remission and

regression of chronic hepatitis and cirrhosis caused by HB-[21] HC- viral

infection.[22]

From the animal models and some case reports, as well as from the recent

clinical studies, the old opinion about the traditional view of cirrhosis as

a progressive irreversible disease is no longer correct. We must accept the

new view of reversal of fibrosis and cirrhosis, when the underlying cause

can be removed and the process of fibrogenesis is stopped by antifibrotic

agents.

http://www.medscape.com/viewarticle/474566_1

[Guest guest]

From Liver International

Clinical, Biochemical and Imaging-Verified Regression of Hepatitis B-Induced

Cirrhosis

Posted 06/02/2004

1Department of Gastroenterology and 2Department of Pathology, Shariati

Hospital, Digestive Diseases Research Center, Tehran University of Medical

Sciences, Tehran, Iran

S. Massarrat; V. Fallahazad; N. Kamalian

Abstract and Introduction

Abstract

In a 65-year-old patient with ascites, jaundice and positive hepatitis B

surface antigen (HBsAg), the histological diagnosis of cirrhosis with

knodell total score 13 was made in 1995. The patient was followed up for 8

years. Spontaneous seroconversion of HBsAg appeared. Except for slight

hyperbilirubinemia, all pathologic, clinical laboratory data remained normal

from the second year of diagnosis till 8 years of follow-up. In the last

follow up, the markers of liver fibrosis were all normal. The portal vein

diameter was decreased and the esophageal varices disappeared. The imaging

of liver by sonography and CT-scan did not reveal any abnormality.

Introduction

Cirrhosis is a diffuse transformation and disorganization of the liver

parenchyma with disturbance of the spatial relationships between portal

tracts and hepatic veins and nodule formation by extensive fibrosis. This

stage of liver disease is considered to be irreversible and the death of

patients due to the complications is unavoidable. There are few reports

about the regression of cirrhosis and resolution of the advanced liver

disease.

We report here about the regression of hepatitis B-induced cirrhosis in a

patient after being followed over 8 years.

Case Report

A 65-year-old patient with a history of diabetes since 16 years treated with

insulin had no problems up to 2.5 months before presenting to us. He got

then jaundice accompanied by general weakness, fever, nausea and vomiting.

After few weeks he felt better, but his abdomen became distended and got

peripheral edema, which is slightly improved by absolute rest. By CT-scan,

small liver with some ascites was verified. By upper gastrointestinal (GI)

endoscopy, grade II esophageal varices were detected. The patient was

admitted in June 1995 in our hospital for diagnosis and treatment of

jaundice and ascites.

By clinical examination, he had jaundice, some distended abdomen and

peripheral edema. He had palmar erythema, no spider angioma was noted. The

liver and spleen were not palpable. His weight was 60 kg.

Following laboratory data were registered: sedimentation rate 20/1 h, Hb

12.3 g/dl, WBC 7000 cells/mm2, hematocrit 35.7%, MCV 88.4 fl, platelet count

110,000/mm2.

Blood sugar 111 mg%, cholesterol 148 mg%, HBsAg positive, hepatitis e

antigen (HBeAg) negative, hepatitis B core antigen (HBcAb) positive. The

results of liver function test are given in Table 1.

By ultrasound exam, the liver was not enlarged, rather small. The

echogenicity was increased. The gallbladder was distended and contained

sludges. Ascites was present. By two times paracentesis 7 l fluid was

removed. Therapy was started with furosemide 40 mg and spironolactone 75 mg

daily. Protein concentration in ascitic fluid was 185 mg% and WBC 50/mm2.

Two weeks after the admission, under i.v. injection of 2 U frozen plasma, a

liver biopsy was taken.

Histologic Finding

Portal areas are enlarged distended to the surrounding lobules, form

portoportal bridges and pseudolobules. Regenerative nodule are present (Fig.

1). Inflammatory mononuclear cells are distended to the marginal plates.

This distention is seen in all zones of parenchymatous lobule and

pseudolobules, rosette formation and piecemeal necrosis are present. The

hepatocytes are swollen; contain ballooning degeneration with marked

deposition of bile in the cytoplasm, bile plugs are noted in bile

canaliculi. The reticuloendothelial cells are proliferated. By special

staining collagen deposits are detected markedly in the portal tracts. The

reticulin is heavily deposited in the sinusoidal walls and in the portal

areas so that the lobular and trabecular pattern are destroyed (Fig. 2).

Immunohistochemical staining for B-virus particles revealed heavy

accumulation in the hepatocytes (Fig. 3). Knodell scoring revealed stage 3-4

and grade 10 (total score was 13-14).

The patient was followed in irregular yearly intervals. He was treated with

Propranolol 40 mg, Spirinolactone 50 mg daily and insulin for his diabetes.

One year later, he had no ascites and jaundice. Two years later and in the

following years all liver function tests were normal except an

hyperbilirubinemia with predominant indirect bilirubin (Table 1).

Abdominal sonography in May 1998 revealed nonenlarged liver with homogenous

structure and increased echogenicity. The anterioposterior angle of the left

lobe was enlarged. The diameter of portal vein with 14 mm was increased. The

spleen had a normal size with a length of 9.7 cm and width of 5.5 cm (Fig.

4). In September 2000, the ultrasound of abdomen showed normal size of liver

by no increased echogenicity. The diameter of portal vein with 11 mm was

normal. The last abdominal sonography in June 2002 revealed normal size of

liver with a homogenous structure and smooth liver surface, and the diameter

of portal vein was 11 mm (Fig. 4B). The CT scan of the liver and spleen

confirmed the sonographic finding with normal size and smooth surface of

liver (Fig. 5). By the last follow-up examination (August 2003) upper GI

endoscopy revealed disappearance of esophageal varices (Fig. 6a, . Severe

antral gastritis with yellow and red patchy areas without hypertensive

gastropathy was verified. The markers of liver fibrosis were determined[1]:

Haptoglobin with 0.66 g/l (normal 0.3-1.53 g/l), Apolipoprotein A1 with 198

mg% (normal 110-200 mg%), ?-Glutamyl transpeptidase with 10 U/l (normal up

to 40 U/l) and ?-globulin with 15.1% (normal </=18%) were all normal.

Discussion

Cirrhosis is an end-stage process of chronic progressive scarring

inflammation caused mainly by viral hepatitis B and C as well as alcohol.

Once cirrhosis established, it has been considered to be irreversible. When

complications of cirrhosis like ascites, severe encephalopathy, jaundice

with variceal bleeding developed, the survival of cirrhotic patients becomes

short and lethality is unavoidable.

Research in the last decade has shown that hepatic fibrosis is a dynamic

process involving deposition and degradation of fibrillar collagens and

other extracellular matrix proteins.[2] Degradation of matrix proteins

occurs by interstitial collagenase regulated by specific molecules called

tissue inhibitors of metalloproteases produced by hepatic stellate

cells.[3-5] The reversibility of hepatic fibrosis seems to be probable and

intensive effort is being made on compounds with antifibrotic agents. The

point at which cirrhosis or extensive fibrosis becomes irreversible, has not

been well-defined.

There are few reports with regard to regression of cirrhosis by intensive

treatment; some patients with autoimmune hepatitis and cirrhosis treated

with immunosuppressive medications responded with regression of

fibrosis.[6,7] Reversal of fibrosis after treatment of hemochromatosis with

phlebotomies was observed in the earlier decades.[8,9] 's disease

after treatment with penicillamine showed normalization of liver

morphology.[10] Regression of fibrosis and cirrhosis were observed in

secondary biliary cirrhosis after biliary decompression,[11,12] and in

primary biliary cirrhosis after treatment.[13]

The regression of cirrhosis is not limited only to cirrhosis with nonviral

etiology. In an hepatology-oriented clinic in Germany, Müting and coworkers

observed regression of cirrhosis in eight of 100 patients with cirrhosis of

different aetiology over a period of 20 years.[14] Resolution of B- and

D-induced cirrhosis over 12 years under interferon therapy[15] and

regression of decompensated liver cirrhosis resulting from B-hepatitis under

lamivudin were the most recent examples.[16] Reversibility of advanced stage

of hepatitis C-induced cirrhosis under combination therapy with pegylated

interferon a-2b and ribavirin is observed, when hepatitis C viremia

cleared.[17]

The course of liver disease in our case shows the regression of cirrhosis

and portal hypertension verified 8 years ago on the base of clinical,

biochemical and abdominal imaging. A liver biopsy specimen taken blindly

from one lobe of liver can give in 21% a false negative result when compared

with laparoscopically obtainable specimens taken under direct view.[18,19]

Therefore, we could only be sure of exact diagnosis, when we were able to

perform laparoscopy to verify the macroscopic and histological regression of

cirrhosis, which was not ethically justified in our patient. The imaging

technique by abdominal ultrasound revealed a regression of increased

echogenicity and decrease of diameter of portal vein. The CT-scan could not

detect any abnormal finding in favor of chronic liver disease.

The regression of cirrhosis and portal hypertension in our patient occurred

by seroconversion of hepatitis B virus by lack of HBeAg without any

therapeutic intervention. We did not measure the titer of HBV-DNA at that

time. Spontaneous clearance of viremia in patients with chronic HBV

infection occurs in 0.4-2% per year in white patients and 0.1-0.8% per year

in Chinese patients.[20] This probably T cell transmitted enhancement of

immune response resulted in clearance of viremia and inducing remission and

regression of chronic hepatitis and cirrhosis caused by HB-[21] HC- viral

infection.[22]

From the animal models and some case reports, as well as from the recent

clinical studies, the old opinion about the traditional view of cirrhosis as

a progressive irreversible disease is no longer correct. We must accept the

new view of reversal of fibrosis and cirrhosis, when the underlying cause

can be removed and the process of fibrogenesis is stopped by antifibrotic

agents.

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