Teaching Clinic: Patients With Non-viral Chronic Liver Diseases Flashcards
Autoimmune hepatitis
- Chronic hepatitis of unknown etiology
- All age groups + both sexes across all ethnic groups
- Female predominance
Variable clinical manifestation:
1. Fluctuating course
2. Asymptomatic / Insidious
3. Acute severe flare
4. Fulminant hepatic failure
Diagnosis:
AIH scoring system: Revised Original Scoring System of the International Autoimmune Hepatitis Group
Immune markers:
- AMA
- ANA, SMA, Anti-LKM1
- Anti-SLA, Anti-actin, Anti-LC1, pANCA
Treatment principles:
1. Specific therapy directed at autoimmune-mediated inflammation
- Immunosuppressives
2. Corticosteroid SE prevention + treatment
3. Cirrhosis-related complications prevention + treatment
Who to treat?
- ALT >10x ULN
- ALT >5x ULN + Serum γ-globulin ≥2x ULN
- Histologic features of bridging necrosis / multiacinar necrosis
- Symptomatic patients
1st line:
Prednisolone + Azathioprine (single-drug / combination)
- Single drug Prednisolone indicated when: cytopenia, TPMT deficiency, malignancy, pregnancy
- Most patients will need long term maintenance therapy
Other immunosuppressive drugs:
- Cyclosporine
- Tacrolimus
- MMF
- Rapamycin
—> Used as salvage therapy
—> Small case series only
—> Expensive
—> Uncertain benefit-to-risk ratio
Liver transplantation:
- Should be considered in patients with decompensated liver cirrhosis
- Outcome after liver transplantation is good
- 5-year survival 80-90%
- 10-year survival ~75%
- Recurrence of autoimmune hepatitis in ~22%
Monitoring:
1. ALT levels (Reduction of disease activity)
2. Serum albumin, PT (Improvement in liver function)
3. Serum γ-globulin levels (suppression of immune response)
4. Serum autoantibody levels (do NOT correlate well with disease activity)
Treatment goals:
1. Normalization of ALT
2. Normalization of γ-globulin levels
3. Normalization of histological activity
- No firm guidelines on how long to treat for and when to stop treatment
- Normalization of ALT does not always indicate normalization of histological activity
- Repeat liver biopsy prior to stopping treatment is recommended
Prognosis:
- Severe untreated AIH can be associated with a very high mortality of up to 50% after 3-5 years of diagnosis
- With correct treatment, life-expectancy can approach that of age-and gender-matched controls
- HCC is rare in autoimmune hepatitis
Azathioprine
- Wide variation in concentrations of active and toxic metabolites due to complex and genetic polymorphisms in metabolizing enzymes
SE:
- Bone marrow suppression
- Cholestatic hepatitis
- Veno-occlusive disease
- Pancreatitis
- Rash
- Severe nausea / abdominal pain
Thiopurine methyltransferase (TPMT) deficiency:
- 1 in 300 patients
- Life-threatening myelotoxicity
NUDT15 genotype testing: (SpC Medicine)
- Decreased function of NUDT15 enzyme —> high level of active metabolites
Primary Biliary Cholangitis
Chronic progressive cholestatic disease of the liver
- Autoimmune etiology:
—> Destruction of intrahepatic bile ducts
—> Progressive ductopenia
—> Progressive cholestasis
—> Fibrosis —> Cirrhosis —> Liver failure
- Middle-aged females predominant
Diagnosis (2 out of 3 = probable diagnosis):
1. Presence of AMA (Antimitochondrial antibodies)
2. Elevation of biochemical markers of cholestasis for >6 months
3. Histological features consistent with diagnosis
Treatment:
1. Specific therapy
- UDCA (Ursodeoxycholic acid) 13-15 mg/kg daily
- Obetiocholic acid 5-10 mg daily
- Immunosuppressive / other drugs
—> Cyclosporine, azathioprine, methotrexate, glucocorticoids
—> Colchicine, D-penicillamine, chlorambucil
—> NO evidence to support their use
- Management of symptoms (Pruritus)
- Cholestyramine (Drug of choice)
- Rifampicin (2nd line)
- Opioid antagonists (Naloxone / Naltrexone / Nalmefene) (3rd line)
- Liver transplantation (intractable cases) - Management of Cholestasis complications
- Osteoporosis / Metabolic bone disease
- Fat-soluble vitamin deficiency
- Hypercholesterolaemia
- Malabsorption - Management of Cirrhosis complications
- Liver transplantation
- Advanced PBC + decompensated disease
—> Mayo risk score, serum bilirubin
—> Intractable pruritus, severe osteoporosis
- Survival rates:1 year 92%, 5 years 85%
- Recurrence rate: 30% at 10 years
Primary Biliary Cholangitis (JC Teaching Clinic)
Epidemiology:
- F:M = 9:1
- Age of symptoms: 40-60 yrs
Clinical features:
1. Pruritus (80%)
- alone (>50%)
- with jaundice (20%)
- postpartum (5%)
2. Jaundice
3. Portal HT
4. Hepatosplenomegaly
5. Incidental discovery (asymptomatic)
6. Others (e.g., fatigue, bone pain)
Signs:
1. Hyperpigmentation
2. Excoriations / Scratch marks
3. Xanthelasmas / Xanthomas
4. Bone tenderness (rare)
Investigations:
1. ↑ ALP + GGT
2. Bilirubin (depends on clinical stages)
3. AST and ALT < 250
4. ↑ Cholesterol
5. ↑ IgM
6. +ve AMA (esp. M2 antigen (>90%))
7. Other autoantibodies
Associated disorders:
- Scleroderma
- Sjogren’s syndrome
- Arthropathy (e.g. RA)
- Thyroiditis
- Renal tubular acidosis
Natural history:
1. Preclinical phase (+ve AMA, normal LFT) (>=2-10 yrs)
2. Asymptomatic (2-20 yrs; indefinite in some)
3. Symptomatic (3-10 yrs)
4. Terminal (0-2 yrs)
Prognosis: depends on bilirubin, albumin, age, ascites
Diagnosis:
1. History, P/E
2. LFT
3. AMA +ve
4. Liver biopsy
5. Exclude
- Extrahepatic obstruction due to stones / RPC (and due to PSC) by USG / ERCP
- Drug-related / Post-viral hepatitis cholestasis
Treatment:
Treat complications
1. Pruritus
- UDCA
- Cholestyramine (may worsen vit D malabsorption)
- Malabsorption of fat-soluble vitamins (Vit A, D, K and Ca)
- Vit A IMI / oral (N.B. Teratogenicity)
- Vit K IMI
- Vit D + Ca orally - Hepatic osteodystrophy
- Vit D / 1,25 diOH D3
- Medium chain triglycerides (MCT) - Steatorrhoea
- ↓ Fat intake
- MCT - Complications of cirrhosis
Treat disease process
1. UDCA (+/- Obeticholic Acid)
2. Liver transplant
UDCA (Ursodeoxycholic acid)
- Increase survival
- Improves serum markers of cholestasis: Bilirubin, ALP, GGT
MOA:
- Exact MOA unknown
- Displaces hepatotoxic bile acids from the bile acid pool (Endogenous bile acids retained in hepatocytes —> damage)
(JC Teaching Clinic:
- Replacement of potentially toxic hydrophobic bile acids
—> Remove Chenodeoxycholic acid + Cholic acid from liver (activate mitochondrial permeability transition pores leading to hepatocyte apoptosis)
- Protect against immune-mediated cholangiocyte apoptosis)
SE:
- GI most common: Stomach ache, diarrhoea
Obetiocholic acid
- Indicated for patients with suboptimal response to UDCA
MOA:
- Complementary mechanisms of action (with UDCA)
- FarnesoidX receptor (FXR) agonist
—> decreases bile acid synthesis
—> increases bile acid secretion
—> anti-inflammatory and anti-fibrotic properties
SE:
- Pruritus
Adverse event:
- Hepatic decompensation (CPT B or C, decompensated cirrhosis)
Cholestyramine, Rifampicin, Opioid antagonist
Cholestyramine:
Oral anion exchange resin
- Binds bile acids —> faecal excretion
- 4g daily —> increase to maximum of 16g daily
- Also potentially binds other drugs
- Ineffective in 10-20%
- SE: GI upsets: dyspepsia, diarrhoea, constipation
Rifampicin:
- Enzyme-inducing antibiotic
- Improves pruritus in cholestasis (150mg bd or tds)
- Potentially hepatotoxic
Naloxone / Naltrexone / Nalmefene:
- Naloxone: very short half life, given IV
- Naltrexone / Nalmefene, longer half life, given orally
Cholestasis complications: Osteoporosis / Metabolic bone disease
BMD should be assessed:
- At time of diagnosis of PBC
- 2 yearly interval thereafter
Treatment:
1. Vit D + Ca supplementation
2. Bisphosphonate therapy if evidence of osteoporosis
- Alendronate
- UDCA has no effect on bone loss
Cholestasis complications: Hypercholesterolaemia
- May not always need treatment
- Increased cholesterol levels associated with cholestasis do NOT increase atherosclerotic risk (HDL disproportionally increases and also lipoprotein X: Antiatherogenic)
Treatment (if familial or other known risk factors)
1. UDCA
- Alone only lowers cholesterol slightly
- Cholestyramine
- May lower cholesterol
- Useful in patient with concomitant pruritus - Statins
- Low HDL cholesterol / other cardiovascular risk factors
- Safe and effective in PBC
Cholestasis complications: Malabsorption
Lipid malabsorption:
- Occurs with steatorrhoea and weight loss
- Reduction in daily dietary fat intake (~40mg)
- Use of medium chain triglycerides
—> Digested + absorbed even with low bile acid concentration
Fat-soluble vitamin deficiency (A, D, E, K):
- Occurs even without steatorrhoea
- Vit D supplementation if biochemical markers of significant cholestasis
- Parenteral Vit K if PT is increased
Wilson’s disease
Autosomal recessive disease of copper metabolism
- ATP7B gene on chromosome 13
—> Encodes transmembrane protein (ATP7B): Copper transporter
—> Defective ATP7B —> Liver copper accumulation
Clinical features:
1. Hepatic
- Persistently elevated serum aminotransferases
- Chronic hepatitis
- Cirrhosis
- Fulminant hepatic failure
-
Neurological
- Tremor
- Choreiform movements
- Parkinsonism
- Gait disturbances
- Dysarthria
- Pseudobulbar palsy
- Dystonia
- Seizures -
Ophthalmic
- Kayser-Fleischer rings
- Sunflower cataracts -
Psychiatric
- Depression
- Neurosis
- Personality changes
- Psychosis
Diagnosis:
NO single test for diagnosis
- Low serum ceruloplasmin (∵ defective ATP7B cannot incorporate Cu onto Apoceruloplasmin to become Ceruloplasmin, Apoceruloplasmin is unstable in blood)
- High 24 hour urinary copper excretion (>1.6 mmol/day)
- Liver biopsy with high copper concentrations (>250 mcg/g dry weight)
- Slit lamp examination for KF rings
- Family screening of 1st degree relatives must be undertaken
Treatment:
1. D-penicillamine, Trientine
- Copper chelators: Promote urinary copper excretion from the body
-
Zinc
- Reduce copper absorption -
Liver transplantation
- Effective cure with good survival
- Disease unresponsive to treatment
- Fulminant hepatic failure
—> Coagulopathy and encephalopathy
—> Coombs-negative haemolytic anaemia (high level of free (non-ceruloplasmin bound) Cu —> direct effect on oxidation of Hb, inhibition of energy-supplying enzymes, direct damage to cell membrane)
—> Rapid deterioration within 8 weeks from onset of illness
- NOT indicated if only for neurologic disease
Monitoring:
1. 24-hr urinary copper excretion
- For chelation therapy (penicillamine / trientine) (200-500mcg denotes adequate treatment)
- For zinc therapy (<125mcg for adequate treatment)
-
Free copper (non-ceruloplasmin bound)
- Target of 50-150 mcg/L -
24-hr zinc level
- For monitoring zinc therapy compliance
D-penicillamine, Trientine
D-penicillamine:
- Promotes urinary excretion of copper
- Worsening of neurological symptoms may occur initially
- Early sensitivity reactions may occur (1-3 weeks)
—> Fever, skin rashes, neutropenia, lymphadenopathy, thrombocytopaenia, proteinuria —> Discontinue
- Late reactions
—> Nephrotoxicity with proteinuria —> Discontinue
- Pyridoxine (Vit B6) 25mg/day should be given to avoid Vit B6 deficiency
Trientine:
- Increasing use of Trientine rather than penicillamine for initial chelation therapy
- 1200-1800mg/d initially; 900-1200mg/d maintenance
- Promotes urinary excretion of copper
- Indicated for those intolerant to penicillamine
- Worsening of neurological symptoms —> Less common than penicillamine
- Fewer SE: Chelates iron —> forms iron complex —> avoid iron supplements
Zinc
- 150mg/d
Main use:
- Maintenance therapy
- Asymptomatic patients
MOA:
Interferes with copper uptake from GI tract:
Induces intestinal metallothionein
—> Binds to copper within duodenal enterocytes
—> When enterocyte is shed during normal cell turnover
—> Loss of faecal copper
—> Creates negative copper balance
Excellent safety profile, Few SE:
- Gastric irritation mainly (10-15%)
- Neurological deterioration uncommon
DDx of Intrahepatic strictures (SpC Medicine)
- Malignancy (e.g. Klaskin tumour)
- RPC
- PSC (usually concomitant with UC / IBD —> arrange colonoscopy)
- IgG4 related disease
- Ketamine-related cholangiopathy
- HIV cholangiopathy
IgG4 disease (SpC Medicine, Phoebe Lam)
- IgG4 = inhibitory isoform of IgG (4 subtypes in total)
—> Asymmetrical: two arms bind to different antigen —> cannot activate —> does not allow other Ig to stick onto it - Typically occur in 6th decade of life
- M>F
Clinical features:
1. Mass
2. Multi-organ involvement:
- Pancreatitis, Cholangitis (Painless jaundice (SpC PP))
- Myocardium
- Eye
- Salivary gland
- Thyroid
- Lymph nodes
- Retroperitoneum mass leading to urinary obstruction
- Kidneys
Investigations:
1. ↑ IgG4:IgG ratio (cutoff: 40%)
2. ↑ IgG4+ plasma cell count (cutoff: 10)
3. Usually only minimally elevated amylase
4. Tissue biopsy
Diagnosis:
1. Clinical suspicion
2. Tissue biopsy (most important: stariform fibrosis)
3. Serum IgG4
Treatment:
1. Short course of steroid (now Rituximab)
2. Monitoring of response: size of mass, serum IgG4 (if not normalized —> start steroid again)
