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Duplicate of Practice Guidelines

Bulgarian Clinical Practice Guidelines on the Diagnosis, Management, and Treatment of Chronic Liver Diseases
(published in Bulgarian Journal of Hepato-gastroenterology in bulgarian language)

2013

BULGARIAN SOCIETY OF GASTROENTEROLOGY, and BULGARIAN ASSOCIATION FOR THE STUDY OF THE LIVER, and BULGARIAN ASSOCIATION FOR METHADONE TREATMENT BULGARIAN INSTITUTE FOR ADDITIONS

I.     Bulgarian clinical practice guidelines on the diagnosis, management, and treatment of Chronic Viral Hepatitis, and Annex: Treatment of chronic viral hepatitis in addicted patients treated with opium agonists and agonist-antagonists. 

     

    Abstract

    I.Chronic hepatitis B (CHB)

      Chronic hepatitis B (CHB) is defined by HBsAg (+) status for more than 6 months with biochemical and histological data for liver injury.

      Required diagnostic steps 

      -          Lab assessment - hematology and blood chemistry panel (АST, АLT, GGT, APh, total protein, albumin, PT, bilirubin, creatinin, glucose, cholesterol, triglycerides;

      -          Serological markers – HBeAg and anti-HBe;

      -          Measurement of serum HBV DNA by quantitative real-time PCR assay;

      -          Liver biopsy (mandatory for patients who are candidates for antiviral therapy). Liver biopsy is not required in patients contraindicated for this procedure as well as in subjects with previously diagnosed liver cirrhosis;

      -          Serological testing for co-infections with HCV; HDV –anti-HDV и anti-НСV antibodies.

      -          Elucidation of concomitant diseases and relevant medical conditions that have to be considered during pretreatment management of patients and choice of treatment strategy - psychiatric disorders, thyroid disorders, obesity, alcohol consumption, drug abuse, chronic renal failure, diabetes mellitus, cardiovascular diseases 

      Indications for treatment of patients with chronic HBV infection 

      The indications for treatment are the same for both HBeAg-positive and HBeAg-negative CHB.

      1.Biochemical activity: elevated serum ALT level > 2x ULN in at least 2 measurements within 6 months.

      2. Viral load: Serum HBV DNA level > 2 000 IU/ml (>10 000 cp/ml)

      3. Severity of liver disease: moderate to severe active necroinflammation and/or at least moderate fibrosis using a standardised scoring system (at least A2 and/or F2 according to METAVIR)

      In patients with serum HBV DNA levels >2 000 IU/ml antiviral treatment may be initiated irrespectively of aminotransferase levels if histological activity of liver disease is above A2 and/or fibrosis grade is above F2 according to METAVIR.

      Patients with compensated cirrhosis and detectable HBV DNA are considered for treatment with nucleotide/nucleoside analogs (NA) even if serum HBV DNA is below 2 000 IU/ml and aminotransferases are within normal range.

      Treatment with NA is indicated in patients with decompensated liver cirrhosis irrespectively of serum HBV DNA level.

      Antiviral therapy is considered also for patients who are non-responders to previous treatment or relapsed during at least 6-month post treatment follow-up. Indications for treatment in these patients are the same as for treatment naïve. Histological assessment is relevant up to 4 years after the last liver biopsy. If liver cirrhosis was established previously there is no need to repeat histological assessment.

      Treatment strategies 

      There are two different treatment strategies for both HBeAg-positive and HBeAg-negative CHB patients: treatment with (PEG-) IFN or NA. 

      -          Treatment with interferon 

      Interferon-alfa therapy (Peg IFN α2a; IFN-a) is indicated mainly in HBeAg (+) patients with high biochemical and histological activity. Better results with interferon based therapy could be achieved in young patients, HBeAg-positive or HBeAg-negative who are with HBV DNA < 10 000 000 IU/ml and without contraindications for IFN. 

      Treatment schedule

      Peg-interferon alfa 2a 180 µg s.c. once weekly for 48 weeks

      In cases with HBV and HDV infection: Interferon-alfa 6 МЕ s.c. three times weekly or Peg-interferon alfa 2a 180 µg s.c. once weekly for 48 седмици. HDV RNA should be measured by PCR assay.

      Assessment of treatment results and follow-up of interferon based therapy  

      At month-3 after initiation of Peg-interferon therapy a control measurement of serum HBV DNA by quantitative PCR assay must be performed for assessment of initial treatment response. If HBV DNA level decreases with more than 1log10 compared to baseline viral load, Peg-interferon therapy continues for total 48 weeks. If there is no initial response treatment with Peg-interferon must be discontinued.

      Viral response at the end of treatment as well as 6-months post therapy is defined by serum HBV DNA level < 2 000 IU/ml. In HBeAg (+) patients additional criteria is achieving of HBeAg-seroconversion. In proportion of patients HBsAg-seroconvertion may be achieved after Peg-interferon discontinuation.

      Patients with CHB on IFN-a or PEG IFN-a  therapy must be monitored according to below chart:

       

      Treatment period

      Post treatment FU* 

       

      baseline 

      Wk 2.

      Wk 4

      Wk 8

      Wk 12

      Wk 16 

      Wk 20

      Wk 24 

      Wk 28

      Wk 32 

      Wk 36 

      Wk 48 

      + 3 months 

      + 6 months 

      Haematology

       

      Hgb

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      RBC

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      WBC (inc differential counting of WBC)  

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Plt

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      Biochmistry

       

      AST

      Х

       

      Х

      Х

      Х

      Х

      Х

      Х

      X

      X

      Х

      Х

      Х

      Х

      ALT

      Х

       

      Х

      Х

      Х

      Х

      Х

      Х

      X

      X

      Х

      Х

      Х

      Х

      GGT

      Х

       

      X

      X

      X

      X

      X

      Х

      X

      X

      X

      Х

      X

      X

      APh

      Х

       

      X

      X

      X

      X

      X

      Х

      X

      X

      X

      Х

      X

      X

      Total protein

      Х

       

       

       

       

       

       

      Х

       

       

       

      Х

       

       

      Albumin

      Х

       

       

       

       

       

       

      Х

       

       

       

      Х

       

       

      Bilirubin

      Х

       

       

       

       

       

       

      Х

       

       

       

      Х

       

       

      Creatinin

      Х

       

       

       

       

       

       

      Х

       

       

       

      Х

       

       

      Glucose

      Х

       

       

       

       

       

       

      Х

       

       

       

      Х

       

       

      TSH,

      anti-TPO (MAT)

      X

      Х

       

       

       

       

       

       

      X

       

       

       

      X

       

       

      Virology

       

      HBeAg/аnti-HBe

      Х

       

       

       

       

       

       

       

       

       

       

      Х

       

      Х

      HBV DNA

      Х

       

       

       

      X

       

       

       

       

       

       

      Х

       

      Х

      HBsAg/anti-HBs

      X

       

       

       

       

       

       

       

       

       

       

       

       

      X

       

      * After sixth month post therapy HBV DNA and aminotransferases must be monitored on 6-month interval up to third year post treatment discontinuation.

      In the light of recent data measurement of serum HBsAg level is initiated as an additional and optional assessment of patients on Peg-interferon alfa 2a therapy at baseline, week 12, 24, 48 and 72.

      Contraindications for interferon-based therapy:

      - decompensated liver cirrhosis

      - severe concomitant cardiovascular and/or respiratory diseases

      - uncontrolled hyper – or hypothyroidisms

      - systemic diseases of connective tissue

      - chronic active bacterial infections

      - neutropenia (<750) and thrombocytopenia (<50 000)

      - psychiatric disorders

      - complicated diabetes mellitus

      - Chronic renal failure without dialysis

      - post organ transplantation

      - pregnancy and lactation

      - HIV co-infection with CD4 <200.  

      -          Treatment with NAs 

      Entecavir (Baraclude) and Tenofovir (Viriad) should be considered as first-line NAs as they are potent HBV inhibitors with a high barrier to resistance. Lamivudinе (Zeffix) is an inexpensive agent, but engenders very high rates of resistance with long-term monotherapy. Telbivudine (Sebivo) is potent HBV inhibitor, expensive, with a low barrier to resistance.

      Indications for treatment with NAs

      Suitable for treatment with NAs (entecavir, tenofovir, lamivudinе, telbivudinе) are patients with:

      -          HBV DNA > 2 000 IU/ml (> 10 000 cp/ml)

      -          liver cirrhosis  (compensated or decompensated) irrespectively of  HBV DNA level

      -          patients on immunosuppressive therapy as well as subjects prior and after organ transplantation irrespectively of  HBV DNA level

      -          HВsAg- negative, but anti HВc-positive subjects with or without positive anti-HВs Ab who are indicated for immunosuppressive therapy. In these cases prophylactic therapy with lamivudine is recommended. This concern  the following patient groups: recipients after organ transplantation who are HBsAg-negative, but anti-HBc – positive or anti-HBc –negative recipients of organ from anti-HBc – positive donor, indicated for systemic chemo radio or immunosuppressive therapy; HBsAg-negative, but anti-HBc – positive patients with IBD, rheumatologic, dermatological diseases who are candidates for anti-TNF therapy.

      -          Pregnant woman with high viral load (HBV DNA > 20 000 000 IU/ml) in the third trimester of pregnancy - lamivudine, telbivudine.

      -          Subjects with renal transplantation who are indicated for NA treatment with lamivudine, telbivudine and entecavir should be used

       

      Treatment schedules for NA therapy 

      -          Entecavir 0,5 mg/daily; 1,0 mg/daily in patients previously treated with lamivudine or in lamivudine-resistant patients.

      -          Tenofovir 300 mg/daily

      -          Lamivudin 100 mg daily

      -          Telbivudine 600 mg daily

       

      The duration of NA therapy is considered on individual basis. Decision is based on viral response and severity of underling liver disease and is approved by expert committee.

      Patients after organ transplantation received prophylactic treatment long life, while the rest patient groups on immunosuppressive therapy – during treatment and 6-months post discontinuation of immunosuppression.   

      In all NAs there is a risk of exacerbation of liver disease in case of drug resistance during therapy as well as after treatment discontinuation. This is associated with risk of severe decompensation of liver disease.  

      Monitoring of patients during NA therapy

      HBV DNA must be measured by quantitative PCR assay at baseline as well as at third month after treatment initiation.

      At month-3 after initiation of NA an assessment of initial treatment response must be performed. If HBV DNA level decreases with less than 1log10 compared to baseline viral load, therapy must be discontinued and the patient have to be switched to another NA after testing for drug resistance.

      Viral response on NA therapy is defined by undetectable serum HBV DNA by real-time PCR assay. If viral response is achieved treatment continues.

      During the treatment the HBV DNA has to be check at 3-month interval for monitoring the patient for viral breakthrough.

      Viral breakthrough is defined by HBV DNA >1log10 of the  is defined as an increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy. It precedes a biochemical breakthrough, characterised by an increase in ALT levels. In case of viral breakthrough testing for drug resistance is mandatory.

      If viral breakthrough occurs it is mandatory to check patient compliance to to antiviral therapy. In compliant patients viral breakthrough must be confirmed by repeated measurement of serum HBV DNA. Further treatment strategy is based on the severity of underling liver disease and proved drug resistance and cross-resistance to NAs. If viral breakthrough occurs during lamivudine add-on therapy with tenofovir or entecavir 1mg/dally should be considered. In case of viral breakthrough on enecavir, patient must be switched to tenofovir. If viral breakthrough occurs during tenofovir, lamivudine should be added to tenofovir.

      Болните с хроничната HBV инфекция на лечение с нуклеозидни/ нуклеотидни аналози се проследяват по схемата:

       

      Treatment period

       

      baseline 

      Month 3 

      Month 6 

      Month 9 

      Month 12

      +every 3 mo.

      End of th

      Haematology

       

      Hgb

      Х

      X

      Х

      X

      Х

      Х

      Х

      RBC

      Х

      X

      Х

      X

      Х

      Х

      Х

      WBC (inc differential counting of WBC)  

      Х

      X

      Х

      X

      Х

      Х

      Х

      Plt

      Х

      X

      Х

      X

      Х

      Х

      Х

      Chemistry

       

      AST

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      AKT

      Х

      Х

      Х

      Х

      Х

      Х

      Х

      GGT

      Х

      X

      X

      X

      Х

      X

      X

      APh

      Х

      X

      X

      X

      Х

      X

      X

      CPK

      X

      X

      X

      X

      X

      X

      X

      Total protein

      Х

      X

      X

      X

      Х

      X

      X

      Albumin

      Х

      X

      X

      X

      Х

      X

      X

      Bilirubin

      Х

      X

      X

      X

      Х

      X

      X

      Creatinin and creatinin clearance

      Х

      X

      X

      X

      Х

      X

      X

      Glucose

      Х

      X

      X

      X

      Х

      X

      X

      Amylase

      Х

      X

      X

      X

      Х

      X

      X

      Virology

       

      HBeAg/аnti-HBe

      Х

       

       

       

      Х*

       

      Х

      HBV DNA

      Х

      Х

      Х

      Х

      Х**

      Х

      Х

      HBsAg/anti-HBs

      X

       

       

       

       

       

      X

      * HBeAg/anti-Hbe should be assessed on 6-month interval; ** HBV DNA should be checked every 3 months

      Patents on telbivudine (Sebivo) have to be monitored additionally for polyneuropathy and myopathy, while those on tenofovir – for renal deterioration (serum creatinine and creatinine clearance).  

      II.                  Chronic hepatitis C (CHC)

        Diagnosis of chronic hepatitis C

        The diagnosis of HCV infection is based on detection of anti-HCV antibodies by enzyme immunoassay and detection of HCV RNA by sensitive molecular method in a patient with signs of chronic hepatitis.

        Pre-therapeutic assessment

        Assessment of liver disease

        The assessment of liver disease should include biochemical markers, such AST, ALT, GGT, AP, bilirubin, prothrombin time or INR, albumin, gammaglobulins, full blood counts. Other biochemical markers are createnin, glucose, cholesterol, 3-glyceroids. In cases with interferon alpha treatment is necessary to investigate TSH and anti-TPO. Abdominal ultrasound must also be performed.

        HCV RNA detection and quantification.

        HCV RNA must be detectable to confirm the causal role of HCV. Serum HCV RNA levels should be expressed in IU/ml to ensure comparability.

        HCV genotypes

        The HCV genotype should be assessed prior to treatment initiation since it influences decisions on the dose of ribavirin and on duration of treatment.

        IL28B polymorphisms (option)

        Host polymorphisms located upstream of the IL28B gene are associated with sustained virological response to treatment with pegylated interferon alpha in combination with ribavirin in patients infected with HCV genotype 1.

        Liver biopsy

        Liver biopsy remains the reference method for assessment of liver disease severity. It is not performed in patients with liver cirrhosis, proven with liver biopsy in the past or with non-invasive methods (ultrasound, endoscopy, CT, MR and others).

        Search for other causes of liver disease

        Co-morbidities, including alcoholic, autoimmune, or metabolic liver disease with steatosis or steatohepatitis should be assessed. It is helpful to exclude preexisting thyroid disease, psychosis, active drug users, severe concurrent medical disease, such as poorly controlled hypertension, heart failure, poorly controlled diabetes and renal failure.

         Indications for treatment.

        -          All treatment-naïve patients with compensated chronic liver disease due to HCV.

        -          Histology finding of liver fibrosis (METAVIR, Knodell/ Ischak).

        -          Patients who failed to eradicate HCV after prior therapy with pegylated IFN-α and ribavirin.

        Contra-indications to therapy.

        Treatment of chronic hepatitis C with interferon containing regimens has contra-indication in the following groups of patients: systemic alcohol abuse; active drug users; liver cirrhosis Child-Pugh B7 or more; heart failure; chronic obstructive pulmonary disease; uncontrolled autoimmune disease; poorly controlled diabetes; renal failure; pregnant women or couples unwilling to comply with adequate contraception; uncontrolled depression, psychosis, or epilepsy; neutrophil count <750/mm³; platelet count <50 000/mm³; hemoglobin <100 g/l; untreated thyroid diseases; poorly controlled hypertension.

        First-line treatment of chronic hepatitis C.

        The first-line treatment of chronic hepatitis C is based on the use of any of the two pegylated IFN-α  (PEGASYS 180 μg; PEG-INTRON 1,5 μg/kg) s.c. administered weekly and daily oral Ribavirin ( <65kg – 800mg; from 65kg to 85kg – 1000mg; >85kg – 1200 mg ).

        Duration of treatment depend from HCV genotype: 6 months in patients with HCV genotype 2 and 3 infection; 12 months in patients with HCV genotype 1, 4, 5 and 6 infection.

        Treatment monitoring 

        During treatment, HCV RNA measurements should be performed at weeks 4, 12 and 24. The end-of-treatment virological response and the SVR 24 weeks after the end of treatment must be assessed.

        Treatment for all HCV genotypes should be stopped at week 12 if the HCV RNA decrease is less than 2 log10 IU/ ml and at week 24 if HCV RNA is still detectable.

        Monotherapy with pegylated IFN-α can be conducted in patients with chronic renal failure on hemodialisis.

        Treatment toxicities should be assessed at weeks 2 and 4 of therapy and at 4-8 weeks intervals thereafter.

        Patients with chronic HCV infection on therapy with pegylated IFN-α and ribavirin are follow-up by the scheme:

         

        Treatment

        Follow up**

        Assay

        B. 

        2w.

        1м.

        2м.

        3м.

        4м. 

        5м.

        6*м. 

        7м.

        8м. 

        9м. 

        12м. 

        + 3м.  

        + 6м.  

        Full blood counts

         

        Hemoglobine

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        RBC

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        WBC

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Platelet count

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Х

        Biochemy

         

        АSТ

        Х

         

        Х

        Х

        Х

        Х

        Х

        Х

        X

        X

        Х

        Х

        Х

        Х

        АLТ

        Х

         

        Х

        Х

        Х

        Х

        Х

        Х

        X

        X

        Х

        Х

        Х

        Х

        GGT

        Х

         

        X

        X

        X

        X

        X

        Х

        X

        X

        X

        Х

        X

        X

        АP

        Х

         

        X

        X

        X

        X

        X

        Х

        X

        X

        X

        Х

        X

        X

        TP

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        Alb.

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        Bil.

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        Createnin

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        Glucose

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        TSH

        Anti-TPO 

        X

        X

         

         

         

        Х

         

         

        X

         

         

         

        X

         

         

        Uric. acide

        Х

         

         

         

         

         

         

        Х

         

         

         

        Х

         

         

        Virology

         

        аnti-HCV

        Х

         

         

         

         

         

         

         

         

         

         

         

         

         

        HCV RNA

        Х

         

        Х

         

        Х

         

         

        X

         

         

         

        Х

         

        Х

        HCV genotype

        Х

         

         

         

         

         

         

         

         

         

         

         

         

         

        **Follow-up of HCV RNA 2 years after the end of treatment

        Treatment safety.

        Flu-like symptoms are often present after pegylated IFN-α injections. Other clinical side effects are severe fatigue, depression, irritability, sleeping disorders, skin reactions and dyspnea. Hematological and biochemical side effects of pegylated IFN-α and ribavirin include neutropenia, anemia, thrombocytopenia, and ALT flares.

        Unusual or severe side effects include seizures, bacterial infections, autoimmune reactions, interstitial lung disease, a neuroretinitis, bone marrow aplasia or idiopathic thrombocytopenia. 

        Treatment dose reductions and stopping rules.

        The pegylated IFN-α dose should be reduced if the absolute neutrophil count falls under 750/mm³, or the platelet count falls below 50 000/mm³, and stopped if the neutrophil count falls below 500/mm³ or the platelet count falls below 25 000/ mm³. When using pegylated IFN-α2a, the dose can be reduced from 180 to 135 μg/week and then to 90 μg/week. When using pegylated IFN-α2b, the dose can be reduced from 1,5 to 1,0 μg/kg/week and then to 0,5 μg/kg/week.

        If hemoglobin <100 g/l occurs, the dose of ribavirin should be adjusted downward by 200 mg at a time, and ribavirin stopped if hemoglobin falls below 85 g/l.

        Triple therapy for HCV genotype 1 infection.

        Boceprevir and telaprevir were the first two and are currently the only protease inhibitors to be approved by the US FDA and the EMA for the treatment of patients infected with HCV genotype 1. When either  of these two protease inhibitors is added to pegylated IFN-α and ribavirin, the SVR rate in treatment naïve patients increases to 70-80%. Boceprevir and telaprevir are also highly effective in patients who fail to achieve a SVR during previous treatment with pegylated IFN-α and ribavirin.

        Telaprevir (750 mg p.o. every 8 hours daily) is initiated along with PEG-IFN/Ribavirin for the first 12 weeks of treatment. Patients then continue PEG-IFN/Ribavirin for a total of either 24 or 48 weeks. Patients, who are treatment naïve or with prior relapse to PEG-IFN/Ribavirin, can be treated for only 24 weeks if they achieve eRVR. Patients who become HCV RNA detectable after week 4 should be treated for a total of 48 weeks (12 weeks of telaprevir triple therapy and 36 weeks of PEG-IFN/Ribavirin). Treatment should be discontinued in any patients with an HCV RNA level > 1000 IU/ml at treatment weeks 4 or 12 and any detectable HCV RNA at treatment week 24.

        The most common adverse events in patients who received telaprevir-based triple therapy included anaemia, nausea, diarrhea, anal-rectal discomfort, rash and pruritus.

        Boceprevir (800 mg p.o. every 8 hours daily) is initiated after 4 weeks of lead-in therapy with PEG-IFN /Ribavirin. After the 4 week lead-in, patients are treated with boceprevir triple therapy.  Patients who are HCV RNA undetectable at treatment week 8 and remain HCV RNA undetectable at treatment week12 and 24 can be treated for a total of 28 weeks. In contrast, patients who become HCV RNA undetectable more than 4 weeks after the addition of boceprevir should be treated for a total of 48 weeks. It is recommended that patients who are interferon resistant, prior non-responders and patients with cirrhosis receive 44 weeks of boceprevir-based triple therapy following the 4 week PEG-IFN /Ribavirin lead-in. Treatment should be discontinued in patients with an HCV RNA level of >100 IU/ml at treatment week 12 and any detectable HCV RNA at treatment weeks 24.

        The most common adverse events in patients who received boceprevir-based triple therapy included anaemia and dysgusea.

          III.                Antiviral therapy in special groups

            -          HIV-coinfection

            -          Thalassemia

            -          Addicted patients treated with opium agonists and agonist-antagonists 

             

            2010

            BULGARIAN SOCIETY OF GASTROENTEROLOGY

            Bulgarian Clinical Practice Guidelines on the Diagnosis, Management, and Treatment 

              I.                Autoimmune liver diseases 

                -          Autoimmune hepatitis

                -          Primary biliary cirrhosis

                -          Overlap-syndrome

                II.                  Toxic hepatitis.

                  -          Drug-induced hepatitis

                  -          Alcoholic liver disease

                  III. Nonalcoholic fatty liver disease

                  IV. Wilson disease

                  V. Idiopathic hemochromatosis

                  VI. Portal hypertension - esophageal and gastric varices, and hypertensive gastropath

                  VII. Ascites, and refractory ascites, and spontaneous bacterial peritonitis, and hepato-renal syndrome

                  VII. Hepatic /portal encephalopathy

                   IX. Primary liver cancer (HCC)

                   X.  Porphyrias

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