Delta Sem (6) - GIT Lecture (11) - Chronic Hepatitis

Chronic Hepatitis Definition

• Liver inflammation lasting more than 6 months

Common Causes

• HCV
• HBV
• Nonalcoholic fatty liver disease (NAFLD)
• Alcohol-related liver disease

Hepatitis C Virus

• Accounts for 60-70% of chronic hepatitis cases
• 75% of acute hepatitis C cases become chronic
• Untreated chronic hepatitis C causes cirrhosis in 20-30% of patients over decades
• The risk of liver cancer increases only if cirrhosis occurs

Hepatitis B Virus

• In adults, 5-10% of hepatitis B cases become chronic, sometimes with hepatitis D coinfection
• In young children, 25-50% of hepatitis B cases become chronic
• Up to 90% of hepatitis B cases become chronic in newborns
• Chronic hepatitis B increases liver cancer risk, regardless of cirrhosis
• Chronic coinfection with Hepatitis B and D viruses leads to up to 70% cirrhosis if untreated

Hepatitis E Virus

• Causes chronic hepatitis in those on immunosuppressants after transplants, cancer treatment or with HIV

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

• Chronic inflammation of the fatty liver
• Formerly called nonalcoholic steatohepatitis (NASH)
• Typically found in obese, diabetic, and/or dyslipidemic individuals

Alcohol-Related Liver Disease

• Typically seen in heavy drinkers
• Characterized by fatty liver and widespread liver inflammation resulting in cirrhosis

Less Common Causes

• Autoimmune hepatitis
• Hemochromatosis
• Wilson Disease
• Medications cause Drug-Induced Liver Injury (DILI), especially with long-term use.
  • Examples include Amiodarone, Isoniazid, Methotrexate, Methyldopa, Nitrofurantoin, Tamoxifen, and Acetaminophen (rarely).
  • Medication-induced liver injury often resolves once stopped
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Celiac disease
• Alpha-1 antitrypsin deficiency

Indications for Suspecting Chronic Hepatitis

• Elevated liver enzymes detected in blood tests
• Previous acute hepatitis
• Adults tested for HCV, as acute HCV is often unrecognized
• People with typical symptoms

Investigations Types

• Liver enzymes (ALT, AST, ALP, GGT) and liver biochemical tests (PT, INR, serum albumin, serum bilirubin)
• Needed for specific diagnosis

Liver Biopsy

• Used to confirm diagnosis, assess inflammation severity (grade), and fibrosis stage (F0-F4: No, mild, advanced, cirrhosis)
• Recently less used, new methods used to detect liver fibrosis stage

Advanced Scans

• Fibroscan (Ultrasound elastography)
• Magnetic resonance elastography

Other Scores

• FIB4
• APRI

Liver Cancer Screening

• For chronic hepatitis B or any cirrhosis, do the following:
  • Abdominal ultrasound every 6 months
  • Measurement of serum alpha-fetoprotein (AFP)

Treatment for Alcohol-Related Liver Disease

• Stop alcohol intake

Treatment for Chronic Hepatitis C

• Use antiviral medications, e.g., Sofosbuvir and Ledipasvir
• Recommended unless life expectancy is short. Treatment duration is 12 weeks
• Effective treatment may eliminate the virus and stop inflammation, preventing cirrhosis

Treatment for MASH

• Focus on managing contributing conditions
• Muscle exercise and diet control for weight loss
• Treatment of diabetes and lipid-lowering drugs
• Avoid drugs like tamoxifen, corticosteroids, and synthetic estrogens, and toxins like pesticides
• Resmetirom tablets with diet and exercise for adults with moderate to advanced liver fibrosis

Treatment for Chronic Hepatitis B

• HBe Ag-positive patients: HBsAg positive >6 months, elevated ALT (>2x normal upper limit), HBV DNA >20,000 IU/ml
• HBe Ag-negative patients: HBsAg positive >6 months, elevated ALT (>2x normal upper limit), HBV DNA >2,000 IU/ml
• Treatment options include Pegylated Interferon (PEG IFN) weekly for 48 weeks

Hepatitis B Drugs

• Nucleoside or nucleotide analogs with no antiviral resistance such as:
  • Lamivudine 100mg/day
  • Adefovir 10 mg daily
  • Entecavir 0.5-1mg/day
  • Telbivudine
  • Tenofovir 300mg tab/day
  • Tenofovir alafenamide 25 mg/day
  • Risk of resistance mutations

Treatment for Complications

• Cirrhosis and liver failure treatments if present

Primary Biliary Cholangitis Definition

• Chronic autoimmune granulomatous inflammation causing Interlobular bile duct damage, leading to cholestasis, fibrosis, cirrhosis, and portal hypertension

Primary Biliary Cholangitis Causes

• Unknown environmental triggers (?pollutants, xenobiotics, non-pathogenic bacteria)
• Genetic predisposition involving IL12A locus, leading to loss of immune tolerance to self-mitochondrial proteins
• Antimitochondrial antibodies (AMA) are hallmark of PBC

Primary Biliary Cholangitis Prevalence

• 4/100,000
• Female:Male ratio is 9:1

Primary Biliary Cholangitis Risk factors

• Positive family history (seen in 1–6%)
• Smoking
• Past pregnancy
• Other autoimmune diseases
• Nail polish/hair dye

Primary Biliary Cholangitis Clinical Picture

• Typical presentation is around age 50
• Often asymptomatic, diagnosed with high alkaline phosphatase enzyme (ALP)
• Lethargy, sleepiness, and pruritus may come years before jaundice
• Signs: jaundice, skin pigmentation, xanthelasma, xanthomata, hepatosplenomegaly

Primary Biliary Cholangitis Complications

• Liver cirrhosis and its consequences, like HCC and osteoporosis
• Malabsorption of fat-soluble vitamins (A, D, E, K), leading to osteomalacia and coagulopathy

Primary Biliary Cholangitis Investigations

• Antimitochondrial antibodies (AMA): M2 subtype positive, titre of 1:40 are in 98% of cases
• Immunoglobulins are high, especially IgM
• High Alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT),mildly increased AST & ALT

Primary Biliary Cholangitis Late Disease signs

• High serum bilirubin, low albumin, prolonged prothrombin time
• Increased cholesterol
• Ultrasound excludes extrahepatic biliary obstruction
• Liver biopsy shows granulomas around bile ducts ± cirrhosis but is not usually needed

Primary Biliary Cholangitis Treatment

• Symptomatic treatment to treat conditions.
  • Pruritus:
    • Cholestyramine 4-8g/24h PO
    • Naltrexone and rifampicin
  • Diarrhea:
    • Codeine phosphate 30mg tab /8h PO
    • Binds to mu-opioid receptors in GIT, lowering intestinal motility to allow more time for fluids and electrolytes to be absorbed, resulting in firmer stools and less frequent bowel movements

Primary Biliary Cholangitis specific treatment

• High-dose Ursodeoxycholic Acid (UDCA) to improve survival and delay liver transplantation
• Fat-soluble vitamin supplementation (A, D, E and K)
• Liver transplantation for end-stage disease or intractable pruritus

Primary Sclerosing Cholangitis Definition

• Inflammation and strictures of intra and extrahepatic bile ducts causing progressive cholestasis

Primary Sclerosing Cholangitis Clinical Presentation

• Pruritus ± fatigue
• Advanced: ascending cholangitis, cirrhosis, hepatic failure
• Typically male, HLA-A1, B8, DR3

Primary Sclerosing Cholangitis Associations

• Autoimmune hepatitis

• 80% also have IBD, usually UC which is associated with a high risk of colorectal malignancy

• Cancers of bile duct, gallbladder, liver, and colon, colonoscopy + ultrasound yearly and cholecystectomy considered for gallbladder polyps

Primary Sclerosing Cholangitis Investigations

• High ALP, GGT, then high bilirubin, hypergammaglobulinemia and/or high IgM
• AMA is negative; ANA, ASMA, and ANCA may be positive
• MRCP shows intra and extrahepatic bile duct strictures
• ERCP to relieve biliary obstruction by stent insertion
• Liver biopsy shows a fibrous, obliterative cholangitis

Primary Sclerosing Cholangitis Treatment

• Cholestyramine 4-8g/24h PO for pruritus
• Can use Naltrexone and Rifampicin for pruritus
• Antibiotics for bacterial cholangitis
• Ursodeoxycholic acid (UDCA) may improve LFT but not survival
• Liver transplant is the mainstay for end-stage disease
  • Recurrence in up to 30%; 5yr graft survival is >60%.
  • Prognosis poor with IBD, as 5–10% develop colorectal cancer post-transplant

Autoimmune Hepatitis Definition

• Inflammatory liver disease of unknown cause characterized by abnormal T-cell function and autoantibodies against hepatocyte surface antigens

Autoimmune Hepatitis Common Demographic

• Young or middle-aged women, bimodal (10–30 or > 40 yrs)

Autoimmune Hepatitis Signs

• Acute hepatitis and signs of autoimmune disease in 40% of individuals
• Fever, malaise, urticarial rash, polyarthritis, pleurisy, pulmonary infiltration, glomerulonephritis

Autoimmune Hepatitis Signs

• Chronic hepatitis in 60% manifests as gradual jaundice or asymptomatic
• Cirrhosis and complications may be present

Autoimmune Hepatitis Types

• Type I:
  • 80% of cases
  • Typical patient: female < 40 years
  • ASMA +ve in 80%, ANA +ve in 10%
  • Increased IgG in 97%
  • 80% respond to immunoregulation
  • 25% present with cirrhosis
  • More common in Europe than the US

Autoimmune Hepatitis Type II

• More often seen in children
• More commonly progresses to cirrhosis and less treatable
• Anti-liver/kidney microsomal type l (LKM1) antibodies +ve
• ASMA and ANA -Ve

Autoimmune Hepatitis Test Results

• Serum bilirubin, AST, ALT, and ALP all usually increased
• Positive auto-antibodies: Anti-smooth muscle antibody (ASMA), Anti-liver kidney microsomal antibody (ALKMA), Antinuclear antibody (ANA), Anti-soluble liver antigen antibody (ASLA)
• Hypergammaglobulinemia (especially IgG)
• Anemia, low WBC, and low platelets indicate hypersplenism
• Liver Biopsy: Interface hepatitis defines autoimmune hepatitis, portal inflammation includes plasma cells
• Present in up to 98% of patients and helps rule other causes
• MRCP help to exclude PSC with disproportionately high ALP

Diagnosis

• Exclude other diseases (no pathognomonic lab tests)
• Criteria based on IgG levels, autoantibodies, and histology without viral disease are helpful
• Overlaps other chronic liver disease which makes diagnosis challenging, such as PBC, PSC, and chronic viral hepatitis

Associations

• Pernicious anemia
• Autoimmune hemolysis
• Ulcerative colitis
• Diabetes mellitus
• Glomerulonephritis
• Autoimmune thyroiditis
• HLA AL, B8, and DR3 haplotype

Autoimmune Hepatitis Treatment

• Immunosuppressive therapy with aim being normal transaminase and IgG concentrations
  • Prednisolone 30 mg/d PO for 1 month, decrease 5mg every month to maintenance dose of 5–10mg/d PO. Can stop after two years, relapse occurs 50–86% -Azathioprine 50–100mg/d orally may be used as a steroid-sparing agent
• Liver transplantation is indicated for decompensated cirrhosis or does not respond to medical therapy
• 10 year survival is 75%
• The presence of cirrhosis at presentation reduces 10yr survival to 62%
• Overlap Syndromes: AIH-PBC has worse outcomes than AIH-PSC

Wilson's Disease Genetics

• Autosomal Recessive disorder due to mutation in CU transporting ATPase,ATP7B gene.
• Rare 3/100,000 inherited disorder of copper (CU) excretion with excess deposition of CU in liver and CNS

General Copper Physiology

• Total body copper 125mg intake: 3mg/day
• In the Liver- copper is incorporated into to caeruloplasmin
• Wilson Disease= copper not transported into caeruloplasmin and released into the Byle

Wilson's Disease Clinical presentation

• CNS manifestations
  • Tremors, Dysarthria, Dystonia, Labile emotion, Increased/Decreased Libido, Decreased Cognition
• Kayser-Fleischer Ring
• Due to CU disposition in Descemet's membrane
• General and Liver signs
  • Non-immune Hemolysis, Blue nails, Arthritis
  • Children- Presents with liver cirrhosis
  • Elevated AST/ALT, Alk PO3
  • Urine Copper high- Normal Copper 14 micro gram/dl is pathognomonic -Molecular: ATP7B gene confirms diagnosis _ Liver biopsy- High Hepatic Copper
• Brain MRI shows degeneration in ganglia, fronto-temporal, cerebellar, and brainstem

Wilson's Disease Management

• 1st Dietary changes:
  • Low high-Copper diets
• 2nd Zine Salts: -Block copper absorption(50 mg 3x )
• 3rd
  • Penicillamine, a chelating agent at 1 divided to 2.4 Daily Doses. -Pyroxidine( B6)
• 4th= Liver Transplantation
• Sibling screening
• Prognosis before cirrhosis is reversible.
• Avoid Tetrahiomolybdate if neurologisymptoms present

Hereditary Haemochromatosis Definition:

• Inherited Disorder of iron metabolism in which excessive intestinal iron absorption leads to the deposition of iron on joints, Liver, Heart, or Reproductive organs.
• Total body iron( 10x that of a normal person). Liver Fibrosis in Late Stages.
• HFE gene is responsible

Hereditary Haemochromatosis Genes

• Most Common Mutations are C282Y and H63-D
• More common in Middle-age men ( Menstration has protection).

Hereditary Haemochromatosis Early and Late Signs

• Early-Tiredness,Decreased Libido
• LATE- Liver Cirrhosis from heavy drinking)

Hereditary Haemochromatosis Diagnostics

• High saturansferrin20ng /mL but inflamateis also elevate

3. HFE genotyping confirms

• MRI shows organ overlap and a Biopsy to quantify

Hereditary Haemochromatosis Treatment

• Dietary control
  • Avoid iron, Limit Alcohol, Avoid uncooked SeaFood that contains infections that raise iron concentratens
• Venesenation to decrease
• Des-ferrioxamine if Vene section can not be be executed
• Monitor Glucose and LFT
• HBAlc- decrease time avail for Gkycosylation
• • Screen for HCC, with ultrasound -60% body iron in hemoglobin , Macrophages transfer

Iron Physiology

• Diet- High iron,Fe 3= reduced to Fe2
• -Hepticicidin negative regulator to iron absorption

Alpha-1 Antitrypsin Deficiency

• Definition: Genetic inheritance deficiency in Alpha- 1 Antiprisent production

Alpha-1 Antitrypsin Deficiency Pathphysiology

• AAT protects from neutrophil elastase( enzyme released in inflammatory situations)leading to destruction of lung tissues
• Abnormal ALT causes misfolded 1-ALT cumulation in the endoplasmicreticulum of the Liver, leading the liver damage.

Alpha-1 Antitrypsin Deficiency Presentation

• Mild Elevated ALT/AST to cirrhosis
• Paticulitis
• Low Serum ALT panel , biopsy shows. pooled-plasma

Non-Alcoholic Liver Fatty Disease

• Accumulation of fat in hepatocytes shows on Ultrasound.
• Check:
  • BMI risk
  • R/O other diseases, then measure Fibroblast

Non-Alcoholic Liver Fatty Disease Control

• Risk Controls and Lower BMI
  • Recommend Resmetirom- THR-B- promotes Liver fat reduction