الحادية عشر GIT الدلتا

• Chronic Hepatitis is defined as inflammation of the liver lasting longer than 6 months.

Causes of Chronic Hepatitis

• Common causes of chronic hepatitis include Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), non-Alcoholic Fatty Liver Disease (NAFLD), and Alcohol-related liver disease.

Hepatitis C Virus

• Accounts for 60 to 70% of chronic hepatitis cases.
• 75% of acute hepatitis C cases progress to chronic hepatitis.
• Untreated chronic hepatitis C leads to cirrhosis in 20-30% of patients over decades.
• Liver cancer risk increases only if cirrhosis is present.

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.
• In newborns, up to 90% of Hepatitis B cases become chronic.
• Chronic hepatitis B increases liver cancer risk whether or not cirrhosis develops.
• Chronic coinfection with hepatitis B and D viruses can cause cirrhosis in up to 70% of untreated cases.

Hepatitis E Virus

• Chronic hepatitis E occurs in individuals taking immunosuppressive drugs after organ transplant, drugs to treat cancer, or with HIV infection.

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

• Characterized as a type of chronic inflammation of the fatty liver.
• Formerly known as nonalcoholic steatohepatitis (NASH).
• Occurs in individuals with obesity, diabetes, and/or dyslipidemia.

Alcohol-Related Liver Disease

• Typically occurs in people who drink heavily for months or years.
• Characterized by fatty liver and widespread liver inflammation resulting in cirrhosis.

Less Common Causes

• Autoimmune hepatitis, Hemochromatosis, and Wilson disease
• Medications, particularly when taken for long time, can cause drug-induced liver injury (DILI).
• Common medications include amiodarone, isoniazid, methotrexate, methyldopa, nitrofurantoin, and tamoxifen; acetaminophen rarely causes this.
• Drug-induced liver injury often resolves after stopping the medication.
• Primary biliary cholangitis, primary sclerosing cholangitis, celiac disease, and alpha-1 antitrypsin deficiency

Investigations of Chronic Hepatitis

Suspect Chronic Hepatitis When

• Blood tests show elevated liver enzymes (regardless of the reason for the blood test)
• A patient had acute hepatitis before
• Adults should be tested for HCV at least once since acute HCV is often unrecognized.
• Patients exhibit typical hepatitis symptoms

Liver Tests to conduct

• Liver enzymes (ALT, AST, ALP, GGT) and liver biochemical tests (PT, INR, serum albumin, serum bilirubin)
• Investigations done for a specific cause: includes liver biopsy to confirm diagnosis and assess severity/stage of inflammation and fibrosis.
• Liver biopsy detects severity of the inflammation (grade), and stage of fibrosis (F0,F1= No fibrosis , F2= mild fibrosis, F3=advanced fibrosis, F4=Cirrhosis)
• FibroScan (Ultrasound elastography) and magnetic resonance elastography are newer methods for detecting liver fibrosis stage.
• FIB4 and APRI scores are used
• Screening for liver cancer is done for patients with chronic hepatitis B or cirrhosis: involves abdominal ultrasound every 6 months and measurement of serum alpha-fetoprotein (AFP).

Treatment of Chronic Hepatitis

Treatment of The Cause

• Alcohol-related liver disease: stop alcohol intake
• Chronic hepatitis C: antiviral medications [(Sofosbuvir + Ledipasvir) recommended for all unless life expectancy is short] for 12 weeks; this eliminates the virus, stops inflammation, and prevents disease progression.
• Treatment of MASH focuses on managing contributing risk factors.
  • Muscle exercise and diet control to lose weight, treatment of diabetes, lipid-lowering drugs, avoiding tamoxifen, corticosteroids, synthetic estrogens, and toxins like pesticides. -Resmetirom tablets with diet and exercise to treat individuals with MASH who have moderate to advanced liver fibrosis.
• Chronic hepatitis B treatment depends on HBeAg status.
  • HBe Ag-positive patients with HBsAg positive for >6 months, elevated ALT levels (>2x upper limit of normal), and HBV DNA > 20,000 IU/ml
  • HBe Ag-negative patients with HBsAg positive for >6 months, elevated ALT levels (>2x upper limit of normal), and HBV DNA > 2000 IU/ml
  • Options - pegylated interferon (PEG IFN) therapy once a week S.C. for 48 weeks or (no antiviral-resistance) nucleoside or nucleotide analogs like Lamivudine100mg/day, Adefovir 10 mg daily, Entecavir.5-1mg/day, Telbivudine, Tenofovir 300mg tab/day, or Tenofovir alafenamide 25 mg/day (development of resistant mutations).

Treatment of Complications

• Cirrhosis and liver failure treatment as needed
• Liver transplantation considered for severe liver failure

Primary Biliary Cholangitis (PBC)

• Chronic autoimmune granulomatous inflammation damages interlobular bile ducts, leading to cholestasis, fibrosis, cirrhosis, and portal hypertension.
• Unknown environmental triggers and genetic predisposition lead to loss of immune tolerance to self-mitochondrial proteins.
• Antimitochondrial antibodies (AMA) are the hallmark of PBC
• Prevalence: 4/100,000; Female:Male ≈ 9:1.
• Risk Factors: Family history, smoking, past pregnancy, other autoimmune diseases, and increased use of nail polish/hair dye.
• Clinical Picture: presentation at around 50 years; patients: asymptomatic and found on accident when testing high alkaline phosphatase enzyme (ALP); lethargy, sleepiness, and pruritus.
• Signs include jaundice, skin pigmentation, xanthelasma, xanthomata, and hepatosplenomegaly.
• Complications: Liver cirrhosis and its complications (including HCC and osteoporosis); malabsorption of fat-soluble vitamins (A, D, E, K) results in osteomalacia and coagulopathy.

Primary Biliary Cholangitis (PBC) Investigations

• Positive antimitochondrial antibodies (AMA): M2 subtype positive, titre of 1:40 occurs in 98% of cases.
• High immunoglobulins, high Alkaline phosphatase (ALP), high gamma glutamyl transferase (GGT), and mildly increased AST & ALT.
• Late disease shows high serum bilirubin, low albumin, prolonged prothrombin time, and increased cholesterol.
• Ultrasound excludes biliary obstruction.
• Biopsy is not usually needed but shows granulomas around bile ducts with/without cirrhosis.

Primary Biliary Cholangitis (PBC) Treatment

• Symptomatic
  • Pruritus Treatment: cholestyramine 4-8g/24h PO or naltrexone and rifampicin.
  • Diarrhea Treatment: codeine phosphate 30mg tab /8h PO; binds to mu-opioid receptors in GIT, decreasing intestinal motility and increasing fluid absorption, effectively reducing diarrhea.
• Specific treatments include high-dose ursodeoxycholic acid (UDCA)” to improve survival and delay liver transplantation and fat-soluble vitamin supplementation (A, D, E and K).
• Liver transplantation is for end-stage disease or intractable pruritus but histological recurrence in graft occurs in approximately 17% after 5 years; graft failure is rare and unpredictable.

Primary Sclerosing Cholangitis (PSC)

• Intra- and extrahepatic bile duct inflammation and strictures result in progressive cholestasis.
• Pruritus +/- fatigue and, if advanced, ascending cholangitis, cirrhosis, and hepatic failure
• Male sex, HLA-A1, B8, DR3, and auto immune hepatitis

• 80% of patients also have IBD, usually UC - associated with high risk of colorectal malignancy.

• Cancers of the bile duct, gallbladder, liver, and colon are common, so regular colonoscopy is needed.
• High ALP and GGT, later followed by high bilirubin
• Hypergammaglobulinemia and/or high IgM may be present.
• AMA is negative while ANA, ASMA, and ANCA may be positive.
• MRCP reveals intra and extrahepatic bile duct strictures while ERCP relieves biliary obstruction with stent insertion.
• Liver biopsy shows fibrous, obliterative cholangitis.

Treatment for Primary Sclerosing Cholangitis (PSC)

• Cholestyramine 4-8g/24h PO for pruritus (naltrexone and rifampicin may also help)
• Antibiotics for bacterial cholangitis.
• Ursodeoxycholic acid (UDCA) can improve LFT results however has not improved survival rates.
• Liver transplant is the mainstay for end-stage disease
• Recurrence occurs in up to 30%, and 5-year graft survival is >60%.

Primary Biliary Cholangitis (PBC) vs Primary Sclerosing Cholangitis (PSC)

Primary Biliary Cholangitis (PBC)

• Inflammation targets intrahepatic bile ducts, leading to fibrosis and cirrhosis.
• Affects more females than males (9:1 ratio)
• Patients are often asymptomatic; can experience pruritus, fatigue, abdominal pain, and jaundice after years
• Cholestatic picture with raised ALP and GGT
• Investigation - Anti-mitochondrial antibody (AMA) M2 subtype positive in 98% of PBC
• Associated conditions include Sjogren's syndrome (seen in 80% of PBC), rheumatoid arthritis, systemic sclerosis, and cirrhosis.
• Managed with cholestyramine for pruritus and ursodeoxycholic acid, which improves survival and delays transplantation.
• Liver transplantation remains an option.

Primary Sclerosing Cholangitis (PSC)

• Inflames both intra- and extrahepatic bile ducts (10-15% only intrahepatic affected)
• Affects more males than females
• Symptoms: pruritus, fatigue, cholangitis

Autoimmune Hepatitis (AIH)

• Inflammatory liver disease of unknown cause characterized by abnormal T-cell function and autoantibodies directed against hepatocyte surface antigens
• Clinical Picture: Occurs in young to middle-aged women (bimodal, i.e.,10–30 or > 40 yrs) and acute hepatitis and signs of autoimmune disease in 40% of patients.
• Patients can experience fever, malaise, urticarial rash, polyarthritis, pleurisy, pulmonary infiltration, or glomerulonephritis with chronic hepatitis in 60% with gradual jaundice or be asymptomatic and diagnosed incidentally with signs of chronic liver disease .
• Amenorrhea is common, and disease severity tends to decrease during pregnancy.
• Patients can develop liver cirrhosis and its complications.

Types of Autoimmune Hepatitis

• Type I: Typical patient is female and < 40 years; ASMA is +ve in 80% and ANA is +ve in 10%. Increased IgG in 97%. Good response to immunosuppression in 80%. 25% have cirrhosis at presentation. Commoner in Europe than UsA.
• Type II: More often seen in children and more commonly progresses to cirrhosis and less treatable. Anti-liver/kidney microsomal type I (LKM1). Antibodies are +ve and ASMA and ANA -ve.

Investigations

• Increased serum bilirubin, AST, ALT, and ALP.
• Positive auto-antibodies like anti-smooth muscle antibody(ASMA), anti-liver kidney microsomal antibody(ALKMA), antinuclear antibody(ANA), and anti-soluble liver antigen antibody(ASLA).
• Hypergammaglobulinemia (esp. IgG) and anemia, a low white cell count with low platelets
• Liver biopsy reveals interface hepatitis (histological hallmark of autoimmune hepatitis) and is characterized by portal inflammation.
• MRCP helps exclude PSC if ALP increases disproportionately

Autoimmune Hepatitis (AIH) Diagnosis, Treatment, and Associations

• Diagnosis depends on excluding other diseases (no lab test is pathognomonic).
• Diagnostic criteria based on IgG levels, autoantibodies, and histology in the absence of viral disease.
• Sometimes diagnosis is a challenge. There is overlap with other chronic liver disease (e.g., PBC, PSC and chronic viral hepatitis).
• Associations: Pernicious anemia, autoimmune hemolysis, ulcerative colitis, diabetes mellitus, glomerulonephritis, OPSC, autoimmune thyroiditis, HLA AL, B8, and DR3 haplotype.
• Immunosuppressive therapy: the first aim of treatment is to normalize transaminase and IgG concentrations.
• Prednisolone 30 mg/d orally(PO) for 1 month, with dose tapering by 5mg every month to a maintenance dose of 5–10mg/d PO.
• Azathioprine (50–100mg/d orally) may be used as a steroid-sparing agent to maintain remission.
• Liver transplantation is indicated for decompensated cirrhosis or if there is failure to respond to medical therapy, but recurrence may occur, and is effective (10yr survival is 75%).

Wilson's Disease (WD)/Hepatolenticular Degeneration

• WD is a rare (3/100 000) inherited disorder of copper (CU) excretion causing excessive copper deposition in the liver and CNS.
• Autosomal recessive disorder is due to mutation in CU transporting ATPase, ATP7B gene.
• Total body copper content is ~125mg with intake ≈ 3mg/day (absorbed in proximal small intestine).
• In the liver, copper is incorporated into caeruloplasmin.
• In Wilson's disease, copper incorporation into caeruloplasmin in hepatocytes and excretion into bile are impaired, so copper accumulates in the liver, and later in other organs.

Wilson's Disease (WD) Clinical Picture

• Clinically presents with liver disease (hepatitis, cirrhosis, fulminant liver failure) in children.
• In young adults who often present with CNS manifestations
  • Tremor, dysarthria, dysphagia, dyskinesias, dystonia, dementia, parkinsonism, ataxia/clumsiness, depression/mania, labile emotions, personality changes, increased or decreased libido, and cognition (decreased memory, slow problem solving, low IQ, delusions, mutism).
• Kayser-Fleischer (KF) ring: due to CU deposition in Descemet's membrane of cornea (may be absent)
• Also presents with non-immune hemolysis, blue lunula (nails), arthritis, hypermobile joints, and grey skin.

Wilson's Disease (WD) Investigations

• Urine: 24h copper excretion is high >100 mcg/24h
• Serum copper: typically <11µmol/L
• Serum ceruloplasmin: <20mg/dL; beware of low values in protein-deficiency states.
• LFT - elevated bilirubin and ALP levels
• Molecular genetic testing detects mutation in ATP7B gene
• Slit lamp exam checks for KF rings
• Liver biopsy: high hepatic copper, hepatitis, and cirrhosis
• MRI: degeneration occurs in basal ganglia, fronto-temporal, cerebellar & brainstem.

Wilson's Disease (WD) Management

• Diet: avoid high copper foods and check water sources.
• Zinc salts: block copper absorption from GIT
• Penicillamine, a CU chelating agent
• Trientine: CU chelating agent
• Tetra-thiomolybdate (TM): copper chelator agent and blocks copper absorption
• Liver transplantation for severe liver disease

Hereditary Hemochromatosis (HH)

• Inherited disorder of iron metabolism in which excessive intestinal iron absorption leads to iron deposition in joints, liver, heart, pancreas, pituitary, adrenals, and skin
• Total body iron ≈10-fold that of a normal person in liver and pancreas
• Gene: HFE
• Mutations: C282Y and H63D
• Affected: Middle-aged men more frequently and severely affected

Hereditary Hemochromatosis (HH) Clinical Picture

• Early: Tiredness, Arthralgia, and Decreased libido
• Later: Slate grey skin pigmentation, signs of chronic liver disease, hepatomegaly, cirrhosis, dilated cardiomyopathy, diabetes mellitus, and hypogonadism

Investigations

• High serum ferritin in male>200/female >150ng/mL, but inflammation also elevates it
• High transferrin saturation >45%