# Implications of liver disease to the oral health care provider
Dr Guru O
Oral Medicine Specialist
#### Clinical Presentation and Professional Overview
Dr. Guru O., an Oral Medicine Specialist, provides an overview of the clinical implications of liver disease within the context of oral health care. This presentation focuses on the systemic considerations and management strategies necessary for dental professionals treating patients with hepatic impairment.
# Functions of the liver
- Functions of liver:
- Storage
- Vitamins – Vit A, D, B12. Lesser amounts of others – vitamin K, B9
- Minerals: Iron in the form of ferritin and hemosiderin and copper.
- Glycogen
- Synthesis
- Circulating proteins (except for gamma globulins)
- Coagulation factors (except for part of factor 8)
- Components of the complement system
- Formation of bile
- Detoxification
- Nitrogenous waste – ammonia converted to urea
- Metabolism
- Hormones
- Drugs
- RBCs
- Glucose, Protein and Lipids
- Surveillance:
- Reticuloendothelial system
#### Storage Functions
- **Vitamins**: Primarily Vitamin A, D, and B12. Lesser amounts of Vitamin K and B9 (folate) are also stored.
- **Minerals**: Iron (stored in the form of ferritin and hemosiderin) and copper.
- **Glycogen**: Storage of glucose for energy regulation.
#### Synthetic Functions
- **Circulating Proteins**: Synthesis of most plasma proteins, with the exception of gamma globulins.
- **Coagulation Factors**: Production of essential clotting factors, excluding a portion of factor VIII.
- **Complement System**: Synthesis of components required for the innate immune response.
- **Bile Formation**: Production of bile necessary for digestion and absorption of fats.
#### Detoxification and Metabolism
- **Nitrogenous Waste**: Conversion of toxic ammonia into urea for excretion.
- **Hormone and Drug Metabolism**: Processing and inactivation of various hormones and pharmacological agents.
- **Red Blood Cell (RBC) Processing**: Breakdown and recycling of aged or damaged red blood cells.
- **Macronutrient Metabolism**: Regulation and processing of glucose, proteins, and lipids.
#### Surveillance and Immunity
- **Reticuloendothelial System**: Active participation in immune surveillance and the removal of pathogens or debris from the bloodstream.
```mermaid
graph TD
A[Precirrhotic disease<br/>10–35 years] --> B[Compensated cirrhosis<br/>10–15 years]
B --> C[Decompensated cirrhosis<br/>3–5 years]
C --> D[Liver transplantation or death]
PE[Precipitating events<br/>Hepatic:<br/>• Excessive alcohol intake<br/>• DILI<br/>• Viral hepatitis A, B, C, D and E<br/>• Ischaemic hepatitis<br/>• TIPS<br/>• Liver surgery<br/>Extrahepatic:<br/>• Acute bacterial infection<br/>• Paracentesis without albumin<br/>• Major surgery<br/>Non-identifiable precipitating event 40–50%]
PE --> ACLF[Acute-on-chronic liver failure]
B --> ACLF
C --> ACLF
ACLF --> AD[Acute decompensation<br/>Organ failure or failures<br/>High short-term mortality]
AD --> OSF[Organ or system failure<br/>• Liver • Coagulation<br/>• Kidney • Circulation<br/>• Brain • Lung]
C --> ADC[Acute decomposition<br/>• Ascites<br/>• Gastrointestinal haemorrhage<br/>• Encephalopathy<br/>• Bacterial infection]
ADC --> OSD[Organ or system dysfunction<br/>• Liver • Kidney • Brain<br/>• Coagulation • Circulation • Heart<br/>• Intestine • Thyroid gland • Lung<br/>• Immune • Adrenal gland • Muscle]
```
#### Stages of Liver Disease Progression
1. **Precirrhotic Disease**: Typically spans a duration of 10–35 years.
2. **Compensated Cirrhosis**: Typically lasts 10–15 years.
3. **Decompensated Cirrhosis**: Typically lasts 3–5 years, leading eventually to liver transplantation or death.
#### Acute Decompensation and Failure
Acute decompensation (ADC) and Acute-on-chronic liver failure (ACLF) represent severe clinical shifts characterized by:
- **Acute Decompensation (ADC)**: Manifests as ascites, gastrointestinal haemorrhage, encephalopathy, and bacterial infection. This leads to multi-system dysfunction affecting the liver, kidneys, brain, heart, thyroid, and immune system.
- **Acute-on-chronic Liver Failure (ACLF)**: Characterized by organ failure (liver, coagulation, kidney, circulation, brain, or lung) and high short-term mortality.
#### Precipitating Events
Events that can trigger rapid decline include:
- **Hepatic Factors**: Excessive alcohol intake, Drug-Induced Liver Injury (DILI), viral hepatitis (A, B, C, D, and E), ischaemic hepatitis, Transjugular Intrahepatic Portosystemic Shunt (TIPS), or liver surgery.
- **Extrahepatic Factors**: Acute bacterial infection, major surgery, or paracentesis performed without albumin.
- **Non-identifiable Events**: In 40–50% of cases, the specific precipitating event remains unknown.
![]()
A flowchart illustrating the natural history of liver disease, showing progression from precirrhotic disease to compensated and decompensated cirrhosis, leading to acute-on-chronic liver failure (ACLF). The diagram includes precipitating events, organ failure, and treatment pathways, with a timeline from 10-35 years to 3-5 years, culminating in liver transplantation or death.
Chronic hepatitis: defined as any hepatitis lasting for 6 months or longer and is classified according to aetiology.
Causes:
- Metabolic: Non-alcoholic fatty liver disease
- Alcohol induced
- Viral:
- Hepatitis B +/- hepatitis D
- Hepatitis C
- Hepatitis E (immunosuppressed)
- Drugs:
- Ketoconazole, idoniazid, nitrofurantoin
- Autoimmune diseases
- Hereditary: Wilsons Disease, Haemochromatosis
- Unusual causes: infections (syphilis, tuberculosis, various tropical infections), infiltrative diseases (amyloidosis and lymphoma), ingestion of toxins
Chronic hepatitis is defined as any inflammatory condition of the liver lasting for six months or longer. It is classified according to its underlying aetiology.
#### Primary Etiological Categories
- **Metabolic**: Non-alcoholic fatty liver disease (NAFLD).
- **Alcohol-Induced**: Liver damage resulting from chronic alcohol consumption.
- **Viral Infections**:
- Hepatitis B (with or without Hepatitis D co-infection).
- Hepatitis C.
- Hepatitis E (primarily observed in immunosuppressed patients).
- **Drug-Induced**: Chronic inflammation caused by medications such as Ketoconazole, Isoniazid, and Nitrofurantoin.
- **Autoimmune**: Liver disease resulting from autoimmune disorders.
- **Hereditary Conditions**: Wilson’s Disease and Haemochromatosis.
#### Unusual and Infiltrative Causes
- **Infections**: Syphilis, tuberculosis, and various tropical infections.
- **Infiltrative Diseases**: Amyloidosis and lymphoma.
- **Toxins**: Ingestion of environmental or chemical toxins.
# Liver diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis/Drug induced liver injury (DILI)
#### Classification of Liver Diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis / Drug induced liver injury (DILI)
# Alcoholic liver disease (ALD)
## 3 histological stages of ALD:
- Alcoholic fatty liver or steatosis – fat accumulation in the liver parenchyma
- Often asymptomatic
- If inflammation or necrosis is seen here – termed steatohepatitis (key here is that its asymptomatic)
- Alcoholic hepatitis – inflammation of the liver cells present
- Alcoholic cirrhosis – irreversible liver damage and leads to complications such as cirrhosis
#### Pathological Progression
1. **Alcoholic fatty liver (Steatosis)**
- Characterized by fat accumulation in the liver parenchyma.
- Often asymptomatic.
- If inflammation or necrosis is present, it is termed steatohepatitis.
2. **Alcoholic hepatitis**
- Characterized by active inflammation of the liver cells.
3. **Alcoholic cirrhosis**
- Involves irreversible liver damage and leads to severe clinical complications.
# Alcoholic liver disease (ALD)
1 standard drink = 10g of ethanol
NHMRC guidelines:
- No more than 4 std drinks per sitting
- No more than 10 std drinks per week
- < 18 should not drink
- Pregnant or breastfeeding should not drink
## Know your standard drinks.
| Beverage Type | Standard Drinks | Alcohol % | Serving Size | Notes |
| --- | --- | --- | --- | --- |
| WHITE WINE | 1.4 | 11.5% | 150ml average serving (about half a glass) | |
| RED WINE | 1.5 | 13% | 150ml average serving (about half a glass) | |
| WINE | 6-8 | 11-13% | 750ml bottle of wine | |
| WINE | 18-21 | 11-13% | 2 litre cask of wine | |
| FULL STRENGTH BEER | 1.1 | 4.8% | 285ml glass (middy/pot) | |
| FULL STRENGTH BEER | 1.6 | 4.8% | 425ml glass (schooner) | |
| FULL STRENGTH BEER | 1.4 | 4.8% | 375ml (can) | |
| FULL STRENGTH BEER | 34 | 4.8% | 24 x 375ml cans | |
| HIGH STRENGTH SPIRITS | 1 | 40% | 30ml nip (shot glass) | |
| READY-TO-DRINK SPIRITS | 1.5 | 5% | 375ml (premix can) | |
| READY-TO-DRINK SPIRITS | 3.6 | 7% | 660ml (large premix bottle) | |
| HIGH STRENGTH SPIRITS | 22 | 40% | 700ml spirit bottle | |
| GLASS OF CHAMPAGNE | 1.4 | 12% | 150ml glass | |
| BOTTLE OF CHAMPAGNE | 7.1 | 12% | 750ml bottle | |
Alcohol (2020) NHMRC
#### NHMRC Consumption Guidelines
One standard drink is defined as 10g of ethanol.
- **General Health:** No more than 10 standard drinks per week and no more than 4 standard drinks per sitting.
- **Under 18s:** Should not consume alcohol.
- **Pregnancy/Breastfeeding:** Should not consume alcohol.
#### Standard Drink Reference Table
| Beverage Type | Standard Drinks | Alcohol % | Serving Size |
| :--- | :--- | :--- | :--- |
| White Wine | 1.4 | 11.5% | 150ml (average serving) |
| Red Wine | 1.5 | 13% | 150ml (average serving) |
| Wine (Bottle) | 6–8 | 11–13% | 750ml |
| Wine (Cask) | 18–21 | 11–13% | 2 Litre |
| Full Strength Beer (Middy/Pot) | 1.1 | 4.8% | 285ml |
| Full Strength Beer (Schooner) | 1.6 | 4.8% | 425ml |
| Full Strength Beer (Can) | 1.4 | 4.8% | 375ml |
| Full Strength Beer (Case) | 34 | 4.8% | 24 x 375ml cans |
| High Strength Spirits (Nip) | 1 | 40% | 30ml |
| Ready-to-Drink Spirits (Can) | 1.5 | 5% | 375ml |
| Ready-to-Drink Spirits (Bottle) | 3.6 | 7% | 660ml |
| High Strength Spirits (Bottle) | 22 | 40% | 700ml |
| Champagne (Glass) | 1.4 | 12% | 150ml |
| Champagne (Bottle) | 7.1 | 12% | 750ml |
![]()
A visual guide titled 'Know your standard drinks' displaying various beverage types with icons and corresponding standard drink counts. The figure includes white wine, red wine, wine bottles, full strength beer, high strength spirits, ready-to-drink spirits, champagne, and their respective alcohol percentages, serving sizes, and standard drink equivalents.
```markdown
Alcoholic liver disease (ALD)
1 standard drink = 10g of ethanol
- Daily consumption of 30-50 grams per day over 5 years can cause alcoholic liver disease
- If your patient drinks >60 grams per day, there is a 90% chance they have steatosis
- If your patient drinks >40g per day, 30% chance they have cirrhosis
(Patel et al 2023)
Know your standard drinks.
| Beverage Type | Alcohol % | Serving Size | Standard Drinks |
|--------------------------|-----------|-----------------------|-----------------|
| WHITE WINE | 11.5% | 150ml average serving (about half a glass) | 1.4 |
| RED WINE | 13% | 150ml average serving (about half a glass) | 1.5 |
| WINE (750ml bottle) | 11-13% | 750ml bottle of wine | 6-8 |
| WINE (2 litre cask) | 11-13% | 2 litre cask of wine | 18-21 |
| FULL STRENGTH BEER (285ml glass) | 4.8% | 285ml glass (middy/pot) | 1.1 |
| FULL STRENGTH BEER (425ml glass) | 4.8% | 425ml glass (schooner) | 1.6 |
| FULL STRENGTH BEER (375ml can) | 4.8% | 375ml (can) | 1.4 |
| FULL STRENGTH BEER (24 x 375ml cans) | 4.8% | 24 x 375ml cans | 34 |
| HIGH STRENGTH SPIRITS (30ml nip) | 40% | 30ml nip (shot glass) | 1 |
| READY-TO-DRINK SPIRITS (375ml) | 5% | 375ml (premix can) | 1.5 |
| READY-TO-DRINK SPIRITS (660ml) | 7% | 660ml (large premix bottle) | 3.6 |
| HIGH STRENGTH SPIRITS (700ml) | 40% | 700ml spirit bottle | 22 |
| GLASS OF CHAMPAGNE | 12% | 150ml glass | 1.4 |
| BOTTLE OF CHAMPAGNE | 12% | 750ml bottle | 7.1 |
Alcohol (2020) NHMRC
```
#### Risk Thresholds for Liver Damage
One standard drink = 10g of ethanol.
- **Alcoholic Liver Disease:** Can be caused by daily consumption of 30–50 grams over 5 years.
- **Steatosis:** 90% probability if consumption exceeds 60 grams per day.
- **Cirrhosis:** 30% probability if consumption exceeds 40 grams per day.
#### Standard Drink Reference Table
| Beverage Type | Alcohol % | Serving Size | Standard Drinks |
| :--- | :--- | :--- | :--- |
| White Wine | 11.5% | 150ml average serving | 1.4 |
| Red Wine | 13% | 150ml average serving | 1.5 |
| Wine (750ml bottle) | 11–13% | 750ml bottle | 6–8 |
| Wine (2 litre cask) | 11–13% | 2 litre cask | 18–21 |
| Full Strength Beer (285ml) | 4.8% | 285ml glass (middy/pot) | 1.1 |
| Full Strength Beer (425ml) | 4.8% | 425ml glass (schooner) | 1.6 |
| Full Strength Beer (375ml) | 4.8% | 375ml can | 1.4 |
| Full Strength Beer (Case) | 4.8% | 24 x 375ml cans | 34 |
| High Strength Spirits (Nip) | 40% | 30ml nip (shot glass) | 1 |
| Ready-to-Drink Spirits (Can) | 5% | 375ml premix can | 1.5 |
| Ready-to-Drink Spirits (Bottle) | 7% | 660ml large premix bottle | 3.6 |
| High Strength Spirits (700ml) | 40% | 700ml spirit bottle | 22 |
| Champagne (Glass) | 12% | 150ml glass | 1.4 |
| Champagne (Bottle) | 12% | 750ml bottle | 7.1 |
![]()
A table titled "Know your standard drinks" displaying various alcoholic beverages with their alcohol percentage, serving size, and equivalent number of standard drinks. The table includes icons representing each beverage type and provides a visual guide to standard drink equivalents for different serving sizes.
What might you see in the chair?
General
- Jaundice
- Smell of alcohol/fetor hepaticus
- Encephalopathy
- Weight loss
Eyes
- Jaundice
- Kayser-Fleischer rings (Wilson's disease)
- Xanthelasma (on eyelids)
Hands
- Flapping tremor
- Palmar erythema
- Dupuytren's contracture (alcohol)
- Nails
- Clubbing
- Leuconychia
Skin
- Scratch marks
Parotid swelling
Spider naevi
Gynaecomastia
Abdomen
- Scars
- Distension (ascites – shifting dullness)
- Dilated superficial veins
- Hepatomegaly (small in cirrhosis)
- Splenomegaly
- Tumour
- Palpable gall bladder
Testicular atrophy
Oedema (pitting)
Bruises
NB: Often patients with liver disease have very few signs.
Randall and Feather 2020
#### Physical Examination Findings
Note: Patients with liver disease often present with very few clinical signs.
- **General Appearance**
- Jaundice
- Smell of alcohol / fetor hepaticus
- Encephalopathy
- Weight loss
- **Eyes**
- Jaundice
- Kayser-Fleischer rings (indicative of Wilson's disease)
- Xanthelasma (on eyelids)
- **Hands**
- Flapping tremor
- Palmar erythema
- Dupuytren's contracture
- Nails: Clubbing or Leuconychia
- **Skin and Body**
- Scratch marks
- Parotid swelling
- Spider naevi
- Gynaecomastia
- Testicular atrophy
- Pitting oedema
- Bruises
- **Abdomen**
- Scars
- Distension (ascites – shifting dullness)
- Dilated superficial veins
- Hepatomegaly (liver may be small in cirrhosis)
- Splenomegaly
- Tumours
- Palpable gall bladder
![]()
A detailed anatomical diagram of a human figure highlighting various clinical signs associated with liver disease. The diagram includes labeled arrows pointing to specific body parts such as the eyes, hands, skin, abdomen, and testicles, each linked to corresponding text boxes describing conditions like jaundice, spider naevi, palmar erythema, and hepatomegaly. Small inset photos illustrate examples of specific signs like spider naevi and palmar erythema.
![]()
A close-up photo of a skin lesion identified as a spider naevus, characterized by a central red spot with radiating blood vessels, located on the upper chest area.
![]()
A close-up photo of an eye showing jaundice, with visible yellowing of the sclera, indicating liver dysfunction.
![]()
A photo of two hands showing palmar erythema, characterized by a reddish discoloration of the palms, a common sign of liver disease.
```markdown
# Specific practice implications for patients with alcohol use disorder....
```html
<table border="1" cellpadding="5" cellspacing="0">
<tr>
<td><b>ACE inhibitors and sartans:</b><br>• e.g. ramipril, perindopril, irbesartan, telmisartan</td>
<td>Alcoholic hepatitis<br>Cirrhosis<br>Especially patients with ascites or renal impairment</td>
<td>Increased risk of interactions with increasing severity of liver disease due to progressive alteration in renal haemodynamics.<br>Commence at a low dose and titrate slowly.<br>The risk of harm in Child-Pugh C cirrhosis may outweigh benefits.</td>
</tr>
<tr>
<td><b>Antibiotics:</b><br>• metronidazole, nitrofurantoin, sulfamethoxazole</td>
<td>Alcohol use disorder</td>
<td>Interaction with alcohol may lead to disulfiram-like reactions (nausea, vomiting, flushing, headache, palpitations).<br>Patients should avoid consuming alcohol during treatment and for 24 hours after finishing the course.<br>Nitrofurantoin may cause drug-induced liver injury.</td>
</tr>
<tr>
<td><b>Opioids:</b><br>• e.g. oxycodone, tramadol, morphine, tapentadol</td>
<td>Alcohol use disorder<br>Cirrhosis<br>Especially patients with history of hepatic encephalopathy</td>
<td>Alcohol consumption enhances the sedative effect of opioids including drowsiness, sedation and impaired motor skills.<br>May precipitate hepatic encephalopathy, especially in patients not taking appropriate laxatives.<br>All slow-release formulations (especially patches) should be avoided due to reversal difficulties if hepatic encephalopathy occurs.<br>If an opioid is indicated, immediate-release tramadol or oxycodone appear safe if commenced at a low dose and titrated slowly.<br>Use paracetamol as an opioid-sparing drug.<br>Avoid tapentadol in Child-Pugh C cirrhosis.</td>
</tr>
</table>
```html
<table border="1" cellpadding="5" cellspacing="0">
<tr>
<td><b>Benzodiazepines:</b><br>• e.g. diazepam, oxazepam, temazepam</td>
<td>Alcohol use disorder<br>Cirrhosis<br>Especially patients with history of hepatic encephalopathy</td>
<td>Alcohol consumption enhances the sedative effect of benzodiazepines including drowsiness, sedation and impaired motor skills.<br>Even short-term use can precipitate hepatic encephalopathy.<br>If a benzodiazepine is indicated, oxazepam or temazepam are preferred due to the comparatively simple hepatic metabolism.</td>
</tr>
<tr>
<td><b>Calcium channel blockers:</b><br>• e.g. felodipine, lercanidipine, verapamil</td>
<td>Cirrhosis<br>Especially patients with symptomatic hypotension or those co-prescribed non-selective beta blockers</td>
<td>If a calcium channel blocker is indicated, amlodipine, nifedipine and diltiazem appear safe if commenced at a low dose and titrated slowly.<br>Felodipine, lercanidipine and verapamil should be avoided in Child-Pugh C cirrhosis.</td>
</tr>
<tr>
<td><b>Non-steroidal anti-inflammatory drugs:</b><br>• e.g. ibuprofen, diclofenac, celecoxib</td>
<td>Alcohol use disorder<br>Alcoholic hepatitis<br>Cirrhosis<br>Especially patients with ascites or renal impairment</td>
<td>Alcohol consumption increases the risk of peptic ulcer disease and gastrointestinal bleeding.<br>Increased risk of renal impairment, acute kidney injury and hepatorenal syndrome in acute and chronic hepatic impairment.<br>All non-steroidal anti-inflammatory drugs should be avoided. Paracetamol is a safe alternative (maximum 2-3 g daily in malnourished patients and those with cirrhosis).</td>
</tr>
</table>
```
#### Medication Management and Interactions
| Drug Class | Condition / Risk Group | Clinical Implications and Recommendations |
| :--- | :--- | :--- |
| **ACE Inhibitors and Sartans** (e.g., ramipril, irbesartan) | Alcoholic hepatitis, Cirrhosis, Ascites, Renal impairment | Increased interaction risk due to altered renal haemodynamics. Start at low dose and titrate slowly. Risk may outweigh benefits in Child-Pugh C cirrhosis. |
| **Antibiotics** (e.g., metronidazole, nitrofurantoin) | Alcohol use disorder | Risk of disulfiram-like reactions (nausea, vomiting, palpitations). Avoid alcohol during and 24 hours after treatment. Nitrofurantoin may cause drug-induced liver injury. |
| **Opioids** (e.g., oxycodone, tramadol, morphine) | Alcohol use disorder, Cirrhosis, Hepatic encephalopathy | Alcohol enhances sedation. May precipitate hepatic encephalopathy. Avoid slow-release formulations/patches. Immediate-release tramadol or oxycodone at low doses are preferred. Use paracetamol as opioid-sparing. Avoid tapentadol in Child-Pugh C. |
| **Benzodiazepines** (e.g., diazepam, oxazepam) | Alcohol use disorder, Cirrhosis, Hepatic encephalopathy | Alcohol enhances sedation and motor impairment. Even short-term use can precipitate encephalopathy. Oxazepam or temazepam are preferred due to simpler metabolism. |
| **Calcium Channel Blockers** (e.g., felodipine, verapamil) | Cirrhosis, Symptomatic hypotension | Amlodipine, nifedipine, and diltiazem appear safe at low doses. Avoid felodipine, lercanidipine, and verapamil in Child-Pugh C cirrhosis. |
| **NSAIDs** (e.g., ibuprofen, diclofenac, celecoxib) | Alcohol use disorder, Alcoholic hepatitis, Cirrhosis | Increased risk of peptic ulcers, GI bleeding, and renal impairment/hepatorenal syndrome. **All NSAIDs should be avoided.** Paracetamol is a safe alternative (max 2–3g daily in cirrhosis/malnutrition). |
![]()
A table detailing the specific practice implications for patients with alcohol use disorder, focusing on benzodiazepines, calcium channel blockers, and non-steroidal anti-inflammatory drugs. It lists drug examples, patient conditions like alcohol use disorder and cirrhosis, and potential risks such as enhanced sedation and hepatic encephalopathy.
![]()
A table outlining the specific practice implications for patients with alcohol use disorder, covering ACE inhibitors and sartans, antibiotics, and opioids. It provides information on drug interactions, risks like disulfiram-like reactions, and recommendations for low-dose titration and avoidance in severe liver disease.
# Liver diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis/Drug induced liver injury (DILI)
#### Common Types of Liver Disease
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis / Drug induced liver injury (DILI)
```markdown
# Nonalcoholic fatty liver disease (NAFLD)
- Most common cause of chronic liver disease in may developed countries
- NAFLD is a spectrum of liver diseases
- Nonalcoholic steatosis (fatty liver) → nonalcoholic steatohepatitis
(no risk of progression) (10-30% may develop cirrhosis or HCC)
Simple fatty change Fat and inflammation → fibrosis and cirrhosis
Cause: thought to be the liver component of metabolic syndrome (obesity, HTN, HLD, T2DM)
Oxidative stress injury (and other factors) leading to lipid peroxidation in the presence of fatty infiltration and inflammation.
Randall and Feather 2020
```
#### Prevalence and Clinical Overview
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in many developed countries.
#### Disease Progression and Spectrum
NAFLD represents a spectrum of liver conditions with varying risks of progression:
- **Nonalcoholic Steatosis (Fatty Liver)**
- Characterized by simple fatty change.
- Generally carries no risk of progression.
- **Nonalcoholic Steatohepatitis (NASH)**
- Characterized by fat and inflammation.
- May lead to fibrosis and cirrhosis.
- Approximately 10–30% of cases may develop cirrhosis or hepatocellular carcinoma (HCC).
#### Etiology and Pathogenesis
- **Metabolic Syndrome:** NAFLD is considered the hepatic component of metabolic syndrome, associated with obesity, hypertension (HTN), hyperlipidemia (HLD), and Type 2 Diabetes Mellitus (T2DM).
- **Oxidative Stress:** Pathogenesis involves oxidative stress injury and other factors leading to lipid peroxidation in the presence of fatty infiltration and inflammation.
# Nonalcoholic fatty liver disease (NAFLD)
- Management:
- Lifestyle advice (weight loss, increased physical activity, attention to cardiovascular risk factors).
- Medical management:
- Orlistat – enteric lipase inhibitor causing malsobroption of dietary fat
- Pioglitazone – (antidiabetic), used for biopsy proven NASH when lifestyle intervention has failed.
- Vitamin E
- Surgical management:
- Bariatric surgery
- Liver translation in NASH cirrhosis
- Monitor for HCC – 2.6% cumulative incidence for patients with NASH,
- Implications: Consider this in patients with metabolic syndrome
Randall and Feather 2020
#### Clinical Management Strategies
- **Lifestyle Interventions:**
- Weight loss.
- Increased physical activity.
- Attention to cardiovascular risk factors.
- **Medical Management:**
- **Orlistat:** An enteric lipase inhibitor that causes malabsorption of dietary fat.
- **Pioglitazone:** An antidiabetic medication used for biopsy-proven NASH when lifestyle interventions have failed.
- **Vitamin E:** Utilized in specific treatment protocols.
#### Surgical and Long-term Care
- **Surgical Interventions:**
- Bariatric surgery.
- Liver transplantation for cases of NASH-related cirrhosis.
- **Monitoring and Surveillance:**
- Regular monitoring for Hepatocellular Carcinoma (HCC), which has a 2.6% cumulative incidence in patients with NASH.
#### Implications for Oral Health Care Providers
Providers should consider the possibility of NAFLD in patients presenting with metabolic syndrome.
# Liver diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis/Drug induced liver injury (DILI)
Common types of liver diseases include:
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis / Drug induced liver injury (DILI)
# Viral Hepatitis
| | A | B | C | D | E |
|---|---|---|---|---|---|
| **Virus** | RNA<br>27 nm<br>*Picornaviridae* | DNA<br>42 nm<br>*Hepadnaviridae* | RNA<br>Approx. 50 nm<br>*Flaviviridae* | RNA<br>36 nm (with HBsAg coat)<br>*Deltaviridae* | RNA<br>27–35 nm<br>*Hepeviridae* |
| **Spread** | | | | | |
| Faeco-oral | Yes | No | No | No | Yes |
| Blood/blood products | Rare | Yes | Yes | Yes | No |
| Vertical | No | Yes | Rare | Occasional | No |
| Saliva | Yes | Yes | Yes | ? No | ? |
| Sexual | Rare | Yes | Yes (rare) | Rare | No |
| **Incubation** | Short (2–3 weeks) | Long (1–5 months) | Long | Intermediate | Short |
| **Age** | Young | Any | Any | Any | Any |
| **Carrier state** | No | Yes | Yes | ? | No |
| **Chronic liver disease** | No | Yes | Yes | Yes | No<sup>a</sup> |
| **Liver cancer** | No | Yes | Yes | Yes | No |
| **Mortality (acute)** | <0.5% | <1% | <1% | <1% | 1–2% (pregnant women 10–20%) |
| **Immunization** | | | | | |
| Passive | Normal immunoglobulin serum i.m. (0.04–0.06 mL/kg) | Hepatitis B immunoglobulin (HBIG) | No | No | No |
| Active | Vaccine | Vaccine | No | HBV vaccine to prevent co-infection | Vaccine |
Randall and Feather 2020
| Feature | Hepatitis A | Hepatitis B | Hepatitis C | Hepatitis D | Hepatitis E |
| :--- | :--- | :--- | :--- | :--- | :--- |
| **Virus Type** | RNA (27 nm) *Picornaviridae* | DNA (42 nm) *Hepadnaviridae* | RNA (~50 nm) *Flaviviridae* | RNA (36 nm with HBsAg coat) *Deltaviridae* | RNA (27–35 nm) *Hepeviridae* |
| **Transmission** | | | | | |
| Faeco-oral | Yes | No | No | No | Yes |
| Blood/products | Rare | Yes | Yes | Yes | No |
| Vertical | No | Yes | Rare | Occasional | No |
| Saliva | Yes | Yes | Yes | ? No | ? |
| Sexual | Rare | Yes | Yes (rare) | Rare | No |
| **Incubation** | Short (2–3 weeks) | Long (1–5 months) | Long | Intermediate | Short |
| **Age Group** | Young | Any | Any | Any | Any |
| **Carrier State** | No | Yes | Yes | ? | No |
| **Chronic Disease**| No | Yes | Yes | Yes | No |
| **Liver Cancer** | No | Yes | Yes | Yes | No |
| **Acute Mortality**| <0.5% | <1% | <1% | <1% | 1–2% (Pregnant: 10–20%) |
| **Immunization** | | | | | |
| Passive | Normal immunoglobulin serum i.m. | Hepatitis B immunoglobulin (HBIG) | No | No | No |
| Active | Vaccine | Vaccine | No | HBV vaccine (prevents co-infection) | Vaccine |
![]()
A comparative table of five types of viral hepatitis (A, B, C, D, E) detailing their characteristics including virus type, transmission routes, incubation period, age susceptibility, carrier state, chronic liver disease, liver cancer risk, mortality, and immunization methods. The table is structured with columns for each hepatitis type and rows for different attributes, providing a comprehensive overview of their differences.
# Implications for the dentist>
## Needlestick injury - Risk of transmission for
- Hep B – 6-30%
- Hep C is 1-3%
## Chance of resolution:
- Hep B – 80% chance of resolution of acute hepatitis, with <20% progressing to a chronic state.
- Hep C – 20% chance of resolution of acute hepatitis, with 80% chance of progressing to a chronic state.
#### Occupational Transmission Risks
The risk of transmission following a needlestick injury varies by virus:
- Hepatitis B: 6–30%
- Hepatitis C: 1–3%
#### Prognosis and Resolution Rates
- **Hepatitis B**: There is an 80% chance of resolution of acute hepatitis, with less than 20% progressing to a chronic state.
- **Hepatitis C**: There is a 20% chance of resolution of acute hepatitis, with an 80% chance of progressing to a chronic state.
# Hepatitis C – testing
- HCV is an RNA virus
- Hence, PCR for RNA is the only method to distinguish chronic vs cleared infection.
- Any patient with +ive HCV RNA should be treated.
#### Diagnostic Methodology
- Hepatitis C (HCV) is an RNA virus.
- PCR for RNA is the only method available to distinguish between a chronic infection and a cleared infection.
- Any patient testing positive for HCV RNA should receive treatment.
```markdown
Hepatitis B – testing
## Hepatitis B Virus Structure
<img src="https://i.imgur.com/placeholder.png" alt="Hepatitis B Virus Structure Simplified to Highlight Serologic Targets.">
Figure 1. Hepatitis B Virus Structure Simplified to Highlight Serologic Targets.
```
#### Hepatitis B Virus Structure
The Hepatitis B virus structure is characterized by specific serologic targets used for diagnostic testing and monitoring.
![]()
A simplified diagram of the Hepatitis B Virus structure, highlighting key serologic targets including HBsAg (surface antigen), HBeAg (E antigen), HBcAg (core antigen), DNA, and DNA polymerase. The diagram shows the virus's concentric layers with labeled components, illustrating the structure relevant to testing and antigen detection.
```markdown
**Acute HBV Infection with Recovery**
**Typical Serologic Course**
**Progression to Chronic HBV Infection**
**Typical Serologic Course**
**Hepatitis B Virus Structure**
Initial screen and testing for Hep B:
• HBsAg – any active infection or carrier state (which can be re-activated)
• Anti-HBs – immunity
• Anti-HBc – any hx of infection
• IgM Anti-HBc – recency of infection and/or detection in surface antigen seronegative window
```
#### Clinical Course and Serology
- Acute HBV Infection with Recovery (Typical Serologic Course)
- Progression to Chronic HBV Infection (Typical Serologic Course)
#### Initial Screening and Testing
The following markers are used for the initial screen of Hepatitis B:
- **HBsAg**: Indicates any active infection or carrier state (which has the potential to be re-activated).
- **Anti-HBs**: Indicates immunity.
- **Anti-HBc**: Indicates any history of infection.
- **IgM Anti-HBc**: Indicates recency of infection; also used for detection during the surface antigen seronegative window.
![]()
A line chart illustrating the typical serologic course of acute HBV infection with recovery, showing the titers of various markers (HBsAg, HBeAg, anti-HBe, IgM anti-HBc, anti-HBs, Total anti-HBc) over weeks after exposure. The chart highlights the progression of markers during the acute phase and recovery, with symptoms occurring around 8-12 weeks.
![]()
A line chart depicting the typical serologic course of progression to chronic HBV infection, showing the titers of HBsAg, HBeAg, anti-HBe, IgM anti-HBc, and Total anti-HBc over years after exposure. The chart illustrates the persistence of HBsAg and HBeAg in the chronic phase, contrasting with the resolution in acute infection.
![]()
A diagram of the Hepatitis B Virus structure, showing the components including HBsAg (surface antigen), HBeAg (E antigen), HBcAg (core antigen), DNA, and DNA Polymerase. The diagram is labeled to highlight the simplified structure for serologic targets.
```markdown
**Acute HBV Infection with Recovery**
**Typical Serologic Course**
**Progression to Chronic HBV Infection**
**Typical Serologic Course**
**Hepatitis B Virus Structure**
Initial screen and testing for Hep B:
- HBsAg – any active infection or carrier state (which can be re-activated)
- Anti-HBs – immunity
- Anti-HBc – any hx of infection
- IgM Anti-HBc – recency of infection and/or detection in surface antigen seronegative window
If HBsAg +ve, further tests:
- HBV DNA (PCR)
- HBeAg
- Anti-Hbe
HBV DNA is the single test that can distinguish between active replicative state – however it is very expensive!
```
#### Clinical Course and Serology
- Acute HBV Infection with Recovery (Typical Serologic Course)
- Progression to Chronic HBV Infection (Typical Serologic Course)
#### Initial Screening and Testing
- **HBsAg**: Any active infection or carrier state (can be re-activated).
- **Anti-HBs**: Immunity.
- **Anti-HBc**: Any history of infection.
- **IgM Anti-HBc**: Recency of infection and/or detection in surface antigen seronegative window.
#### Supplemental Testing for HBsAg Positive Patients
If a patient is HBsAg positive, further tests are required:
- HBV DNA (PCR)
- HBeAg
- Anti-Hbe
#### Replicative State Identification
HBV DNA is the single test capable of distinguishing an active replicative state; however, it is very expensive.
![]()
A line graph showing the typical serologic course of acute HBV infection with recovery, illustrating the progression of various markers (HBsAg, HBeAg, anti-HBe, IgM anti-HBc, anti-HBs) over weeks after exposure, with a peak in IgM anti-HBc and a decline in HBsAg.
![]()
A line graph depicting the typical serologic course of progression to chronic HBV infection, showing the persistence of HBsAg and HBeAg over years, with a decline in IgM anti-HBc and the appearance of anti-HBe, indicating chronic infection.
![]()
A simplified diagram of the Hepatitis B Virus structure, labeling key components such as HBsAg (surface antigen), HBeAg (E antigen), HBcAg (core antigen), DNA, and DNA polymerase, arranged in a concentric structure.
# Liver diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis/Drug induced liver injury (DILI)
Liver diseases encompass a variety of conditions that impact oral health care considerations, including:
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis / Drug induced liver injury (DILI)
# Autoimmune hepatitis
**Description**: immune mediated inflammatory disease of the liver characterized by circulating Abs, increased concentration of IgG and distinctive histological features.
**Epidemiology**:
- Gender: 4:1 F predominance
- Age: >18
- Race: higher in Europeans and US (Caucasian background, but can be anyrone)
- Incidence: 1 per 100 000
- Prevalence: 22.8 per 100 00
**Etiology**: multifactorial – genetic factors, altered immune tolerance, environment (smoking, toxins), individual risk factors, viral infection, DILI
**Pathogenesis**: antibodies against proteins expressed in liver cells
**Diagnosis**: bloods (exclude other hepatitis), ultrasound and liver biopsy
**Management**:
- Prednisolone – bridging therapy – 0.5mg/kg or upto 1.0 mg/kg for acute cases
- Azapthioprine first line
- Mycophenolate mofetil second line
Muratori et al 2023
#### Disease Description and Pathogenesis
Autoimmune hepatitis is an immune-mediated inflammatory disease of the liver. It is characterized by circulating antibodies (Abs), increased concentrations of IgG, and distinctive histological features. The pathogenesis involves antibodies directed against proteins expressed in liver cells.
#### Epidemiology
- **Gender**: Significant female predominance (4:1 ratio)
- **Age**: Typically affects individuals over 18 years of age
- **Race**: Higher prevalence in Europeans and individuals in the US of Caucasian background, though it can affect any population
- **Incidence**: 1 per 100,000
- **Prevalence**: 22.8 per 100,000
#### Etiology and Risk Factors
The etiology is multifactorial, involving:
- Genetic factors
- Altered immune tolerance
- Environmental triggers (e.g., smoking, toxins)
- Individual risk factors
- Viral infections
- Drug-induced liver injury (DILI)
#### Diagnosis
Diagnosis is achieved through a combination of:
- Blood tests (to exclude other forms of hepatitis)
- Ultrasound imaging
- Liver biopsy
#### Clinical Management
- **Prednisolone**: Used as bridging therapy; dosage is typically 0.5 mg/kg, increasing up to 1.0 mg/kg for acute cases.
- **Azathioprine**: Utilized as the first-line treatment.
- **Mycophenolate mofetil**: Utilized as a second-line treatment option.
# Liver diseases
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis/Drug induced liver injury (DILI)
Common types of liver diseases include:
- Alcoholic liver disease
- Nonalcoholic fatty liver disease (NAFLD)
- Viral Hepatitis
- Autoimmune hepatitis
- Drug induced hepatitis / Drug induced liver injury (DILI)
It must be considered in the cirrhotic patient; hepatic reserve is limited in the event of DILI.
Hence, prescribing any drugs with potential hepatotoxicity should be done with caution, as any drug related hepatic injury may precipitate decompensation.
#### Considerations for Cirrhotic Patients
Drug Induced Liver Injury (DILI) must be considered in the cirrhotic patient, as hepatic reserve is limited.
Prescribing any drugs with potential hepatotoxicity should be done with caution. Any drug-related hepatic injury may precipitate decompensation in these patients.
```markdown
What is Drug Induced liver injury (DILI)?
• Definition: acute or chronic liver response to a natural or manufactured compound (Francis 2022)
• Can be categorised by:
• LFTs
• Histology
• Acute vs chronic
• Pathogenesis:
• Direct/Intrinsic – predictable and dose dependent
• Indirect/Idiosyncratic – unpredictable and non dose dependent
```
#### Definition and Categorization
Drug Induced Liver Injury (DILI) is defined as an acute or chronic liver response to a natural or manufactured compound (Francis 2022). It can be categorized by:
- Liver Function Tests (LFTs)
- Histology
- Acute vs. chronic presentation
#### Pathogenesis Mechanisms
- **Direct/Intrinsic**: Predictable and dose-dependent.
- **Indirect/Idiosyncratic**: Unpredictable and non-dose dependent.
What is Drug Induced liver injury (DILI)?
- Definition: acute or chronic liver response to a natural or manufactured compound (Francis 2022)
- Signs and symptoms: jaundice, weakness, abdominal pain, dark stools or urine, nausea, pruritis
- Treatment
- withdrawal of offending agent
- N-acetyl cysteine (NAC) for treatment of paracetamol toxicity (regeneration of glutathione)
- Steroid for DILI resembling AIH
- Inpatient assessment if ALF suspected
#### Clinical Presentation
Common signs and symptoms of DILI include:
- Jaundice
- Weakness
- Abdominal pain
- Dark stools or urine
- Nausea
- Pruritis
#### Treatment Protocols
- Withdrawal of the offending agent.
- Administration of N-acetyl cysteine (NAC) for paracetamol toxicity to facilitate regeneration of glutathione.
- Steroid therapy for DILI cases resembling Autoimmune Hepatitis (AIH).
- Inpatient assessment if Acute Liver Failure (ALF) is suspected.
So which drugs are hepatotoxic?.......
Identification of specific hepatotoxic drugs is essential for clinical management.
# Drug induced liver injury
LiverTox: An Online Resource for Information on Drug-induced Liver Injury
Research Update April 1, 2022
4 categories of likelihood causing liver injury:
- Category A > 50 published reports
- Category B >12 but <50
- Category C > 4 but <12
- Category D 1-3 case reports
- Category E – no implication
Bjornsson 2016
#### LiverTox Resource and Likelihood Categories
LiverTox serves as an online resource for information on Drug-Induced Liver Injury (Research Update April 1, 2022). Drugs are classified into five categories based on the likelihood of causing liver injury (Bjornsson 2016):
- **Category A**: > 50 published reports
- **Category B**: > 12 but < 50 published reports
- **Category C**: > 4 but < 12 published reports
- **Category D**: 1–3 case reports
- **Category E**: No implication
![]()
A screenshot of a webpage from LiverTox, an online resource for information on drug-induced liver injury, showing a research update dated April 1, 2022. The page includes a navigation bar with links to Home, News, and News Archive, and a title section with the resource's name and update date.
# Drug induced liver injury
## Category A > 50 published reports
| Drug | Drug Class/Indication |
| :--- | :--- |
| 1. Allopurinol | Gout prophylaxis |
| 2. Amiodarone | Arrhythmia |
| 3. Amoxicillin-clavulanate | Antibiotic |
| 4. Anabolic steroids | Body building |
| 5. Atorvastatin | Lipid lowering agent |
| 6. Azathioprine/6-Mercaptopurine | Immunosuppressive agent |
| 7. Busulfan | Malignancy |
| 8. Carbamazepine | Antiepileptic |
| 9. Chlorpromazine | Psychosis |
| 10. Contraceptives | Birth control |
| 11. Dantrolene | Muscle relaxant |
| 12. Diclofenac | NSAID |
| 13. Didanosine | Antimicrobial |
| 14. Disulfiram | Substance abuse agent |
| 15. Efavirenz | Antimicrobial |
| 16. Erythromycin | Antimicrobial |
| 17. Floxuridine | Antineoplastic |
| 18. Flucloxacillin | Antimicrobial |
| 19. Flutamide | Antineoplastic |
| 20. Gold salts | Immunosuppressive agent |
| 21. Halothane | Anaesthetic |
| 22. Hydralazine | Antihypertensive |
| 23. Ibuprofen | NSAID |
| 24. Infliximab | Immunosuppressive agent |
| 25. Interferon alpha/Peginterferon | Antimicrobial |
| 26. Interferon beta | Multiple Sclerosis |
| 27. Isoniazid | Antituberculosis |
| 28. Ketoconazole | Antifungal |
| 29. Methotrexate | Immunosuppressive agent |
| 30. Methylpoda | Antihypertensive |
| 31. Minocycline | Antibiotic |
| 32. Nevirapine | Antimicrobial |
| 33. Nimesulide | NSAID |
| 34. Nitrofurantoin | Antibiotic |
| 35. Phenytoin | Antiepileptic |
| 36. Propylthiouracil | Antithyroid |
| 37. Quinidine | Arrhythmia |
| 38. Pyrazinamide | Antituberculosis |
| 39. Rifampin | Antituberculosis |
| 40. Simvastatin | Lipid lowering agent |
| 41. Sulfamethoxazole/Trimethoprim | Antibiotic |
| 42. Sulfazalazine | Antibiotic |
| 43. Sulfonamides | Antibiotic |
| 44. Sulindac | NSAID |
| 45. Telithromycin | Antibiotic |
| 46. Thioguanine | Antineoplastic |
| 47. Ticlopidine | Platelet inhibitor |
| 48. Valproate | Antiepileptic |
## Of note:
- Amoxicillin-clavulanate
- Azathioprine
- Carbamazepine
- Diclofenac
- Erythromycin
- Ibuprofen
- Methotrexate
- Minocycline
- Sulfamethoxazole/Trimethoprim
Bjornsson 2016, Chalasani et al 2015
#### Category A Drugs (> 50 Published Reports)
| Drug | Drug Class/Indication |
| :--- | :--- |
| 1. Allopurinol | Gout prophylaxis |
| 2. Amiodarone | Arrhythmia |
| 3. Amoxicillin-clavulanate | Antibiotic |
| 4. Anabolic steroids | Body building |
| 5. Atorvastatin | Lipid lowering agent |
| 6. Azathioprine/6-Mercaptopurine | Immunosuppressive agent |
| 7. Busulfan | Malignancy |
| 8. Carbamazepine | Antiepileptic |
| 9. Chlorpromazine | Psychosis |
| 10. Contraceptives | Birth control |
| 11. Dantrolene | Muscle relaxant |
| 12. Diclofenac | NSAID |
| 13. Didanosine | Antimicrobial |
| 14. Disulfiram | Substance abuse agent |
| 15. Efavirenz | Antimicrobial |
| 16. Erythromycin | Antimicrobial |
| 17. Floxuridine | Antineoplastic |
| 18. Flucloxacillin | Antimicrobial |
| 19. Flutamide | Antineoplastic |
| 20. Gold salts | Immunosuppressive agent |
| 21. Halothane | Anaesthetic |
| 22. Hydralazine | Antihypertensive |
| 23. Ibuprofen | NSAID |
| 24. Infliximab | Immunosuppressive agent |
| 25. Interferon alpha/Peginterferon | Antimicrobial |
| 26. Interferon beta | Multiple Sclerosis |
| 27. Isoniazid | Antituberculosis |
| 28. Ketoconazole | Antifungal |
| 29. Methotrexate | Immunosuppressive agent |
| 30. Methylpoda | Antihypertensive |
| 31. Minocycline | Antibiotic |
| 32. Nevirapine | Antimicrobial |
| 33. Nimesulide | NSAID |
| 34. Nitrofurantoin | Antibiotic |
| 35. Phenytoin | Antiepileptic |
| 36. Propylthiouracil | Antithyroid |
| 37. Quinidine | Arrhythmia |
| 38. Pyrazinamide | Antituberculosis |
| 39. Rifampin | Antituberculosis |
| 40. Simvastatin | Lipid lowering agent |
| 41. Sulfamethoxazole/Trimethoprim | Antibiotic |
| 42. Sulfazalazine | Antibiotic |
| 43. Sulfonamides | Antibiotic |
| 44. Sulindac | NSAID |
| 45. Telithromycin | Antibiotic |
| 46. Thioguanine | Antineoplastic |
| 47. Ticlopidine | Platelet inhibitor |
| 48. Valproate | Antiepileptic |
#### Notable Hepatotoxic Agents
Of particular note in clinical practice (Bjornsson 2016, Chalasani et al 2015):
- Amoxicillin-clavulanate
- Azathioprine
- Carbamazepine
- Diclofenac
- Erythromycin
- Ibuprofen
- Methotrexate
- Minocycline
- Sulfamethoxazole/Trimethoprim
![]()
A table listing drugs associated with Category A drug-induced liver injury, with over 50 published reports. The table includes two columns: 'Drug' and 'Drug Class/Indication', listing various medications such as Allopurinol, Amiodarone, and Amoxicillin-clavulanate, along with their respective classes or indications like gout prophylaxis, arrhythmia treatment, and antibiotic use.
![]()
A bulleted list titled 'Of note' highlighting specific drugs that are particularly relevant in the context of drug-induced liver injury. The list includes Amoxicillin-clavulanate, Azathioprine, Carbamazepine, Diclofenac, Erythromycin, Ibuprofen, Methotrexate, Minocycline, and Sulfamethoxazole/Trimethoprim.
Jaundice
Jaundice is a clinical manifestation of elevated bilirubin levels in the blood, resulting in the yellowing of the skin and mucous membranes.
# Bilirubin
## Physiology of bilirubin:
- Conversion of heme to bilirubin is a 2-step process:
- 1st step: heme (from erythrocyte) → biliverdin
- Mainly spleen
- 2nd step: biliverdin → unconjugated bilirubin (UCB)
- Mainly spleen
- UCB is transported in blood by albumin
- Entry into hepatocytes
- In hepatocytes:
- Unconjugated bilirubin gets conjugated with glucuronic acid
- Conjugated bilirubin then gets secreted into bile
Singh et al 2023
#### Bilirubin Production and Initial Processing
The conversion of heme to bilirubin is a two-step process:
1. **Heme to Biliverdin**: Heme (derived from erythrocytes) is converted to biliverdin, occurring mainly in the spleen.
2. **Biliverdin to Unconjugated Bilirubin (UCB)**: Biliverdin is converted to unconjugated bilirubin, also primarily in the spleen.
#### Transport and Hepatic Processing
- **Transport**: UCB is transported through the bloodstream bound to albumin.
- **Hepatocyte Entry**: UCB enters the hepatocytes.
- **Conjugation**: Inside the hepatocytes, unconjugated bilirubin is conjugated with glucuronic acid.
- **Secretion**: Conjugated bilirubin is then secreted into the bile.
```markdown
# Bilirubin
## Physiology of bilirubin:
- Conjugated bilirubin is water soluble and is excreted out of the bile duct into the middle duodenum.
- Conjugated bilirubin is broken down by gut flora to **urobilinogen**. This can be:
- Excreted in stool as **stercobilinogen**
- Reabsorbed via the enterohepatic circulation (portal vein), after which:
- Liver excretes it back into bile duct with bile salts OR
- It enters the circulation and is excreted through the kidneys
Singh et al 2023
```
#### Excretion and Metabolism of Conjugated Bilirubin
- **Duodenal Secretion**: Conjugated bilirubin is water-soluble and is excreted via the bile duct into the middle duodenum.
- **Breakdown by Gut Flora**: In the intestines, conjugated bilirubin is broken down by gut flora into **urobilinogen**.
#### Pathways of Urobilinogen
Urobilinogen follows one of two primary pathways:
1. **Stool Excretion**: It is excreted in the stool as **stercobilinogen**.
2. **Enterohepatic Circulation**: It is reabsorbed via the portal vein, after which:
- The liver excretes it back into the bile duct along with bile salts, OR
- It enters the systemic circulation and is excreted through the kidneys.
```html
<table>
<tr>
<td>UNCONJUGATED BILIRUBIN</td>
<td>→</td>
<td>LIVER</td>
<td>→</td>
<td>CONJUGATED BILIRUBIN</td>
</tr>
</table>
```
#### Summary of Hepatic Transformation
- **UNCONJUGATED BILIRUBIN** → **LIVER** → **CONJUGATED BILIRUBIN**
![]()
A flow diagram illustrating the metabolic pathway of bilirubin, showing the conversion of unconjugated bilirubin to conjugated bilirubin via the liver. The process is depicted with text labels and arrows indicating the direction of transformation.
# Excess unconjugated bilirubin
- Increase in bilirubin production:
- Increased breakdown of heme
- Due to accelerated or prolonged hemolysis
- Large hematoma
- Impaired bilirubin uptake
- Decrease bilirubin delivery to the liver (reduced hepatic flow) e.g. congestive heart failure and portosystemic shunts.
- Inefficient uptake of bilirubin by hepatocytes - e.g. drugs or contrast administration
- Impaired bilirubin conjugation
- Within hepatocytes – from hereditary defects (Gilbert syndrome and Crigler-Najjar syndrome).
Singh et al 2023
#### Increased Bilirubin Production
This occurs due to the increased breakdown of heme, which can be caused by:
- Accelerated or prolonged hemolysis.
- Large hematomas.
#### Impaired Bilirubin Uptake
- **Reduced Hepatic Flow**: Decreased delivery of bilirubin to the liver (e.g., congestive heart failure or portosystemic shunts).
- **Inefficient Hepatocyte Uptake**: Interference with the uptake process, often due to drugs or the administration of contrast agents.
#### Impaired Bilirubin Conjugation
This involves defects within the hepatocytes, often resulting from hereditary conditions such as:
- Gilbert syndrome.
- Crigler-Najjar syndrome.
Excess conjugated bilirubin
- Extrahepatic cholestasis:
- Due to biliary duct obstruction (due to primary sclerosing cholangitis, AIDS cholangiopathy etc)
- Pressure from the obstructed bile duct allows conjugated bilirubin to overcome resistance of tight junctions in the hepatocytes and reflux into the plasma
- Intrahepatic cholestasis:
- Aberrations in conjugated bilirubin transport, bile canalicul ar membrane fluidity and hepatocyte cytoskeletal function – these deviations are caused by a myriad of processes, usually hereditary.
- Dubin-Johnson syndrome – defect in the MRP2 protein.
- Hepatocellular injury:
- Release of intracellular proteins into the plasma.
- Acute hepatitis
- Chronic hepatitis – cirrhotic
Tripathi et al 2023)
#### Extrahepatic Cholestasis
- **Biliary Obstruction**: Caused by conditions such as primary sclerosing cholangitis or AIDS cholangiopathy.
- **Mechanism**: Pressure from the obstructed bile duct allows conjugated bilirubin to overcome the resistance of hepatocyte tight junctions, resulting in reflux into the plasma.
#### Intrahepatic Cholestasis
- **Transport and Structural Defects**: Involves aberrations in conjugated bilirubin transport, bile canalicular membrane fluidity, and hepatocyte cytoskeletal function.
- **Hereditary Factors**: These deviations are often caused by hereditary processes, such as:
- **Dubin-Johnson syndrome**: A specific defect in the MRP2 protein.
#### Hepatocellular Injury
Injury to the liver cells leads to the release of intracellular proteins into the plasma. Common causes include:
- Acute hepatitis.
- Chronic hepatitis (cirrhotic stage).
# Summary and key points for patients with liver disease
- Be mindful of DILI in patients with cirrhosis (antibiotics, NSAIDs paracetamol dosage) – they have limited hepatic reserve
- Special drug consideration for patients with alcohol use disorder
- Query bleeding in cirrhotic patient – clotting ability and risk of variceal bleeding
- Antibiotic prophylaxis may be considered for patients with ascites to prevent bacterial peritonitis – discuss with medical GP
#### Medication and Drug Considerations
- Be mindful of Drug-Induced Liver Injury (DILI) in patients with cirrhosis, particularly regarding the use of antibiotics, NSAIDs, and paracetamol dosages, as these patients have limited hepatic reserve.
- Apply special drug considerations for patients with alcohol use disorder.
#### Bleeding Risks and Complications
- Query bleeding risks in cirrhotic patients, specifically assessing clotting ability and the risk of variceal bleeding.
#### Infection Control and Prophylaxis
- Antibiotic prophylaxis may be considered for patients with ascites to prevent spontaneous bacterial peritonitis; this should be discussed with the patient's medical GP.
# References
- Alcohol (2020) NHMRC. Available at: https://www.nhmrc.gov.au/health-advice/alcohol (Accessed: 23 January 2025).
- Arroyo, V., Moreau, R., Kamath, P. et al. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers 2, 16041 (2016). https://doi.org/10.1038/nrdp.2016.41
- Björnsson ES. Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int J Mol Sci. 2016 Feb 6;17(2):224. doi: 10.3390/ijms17020224. PMID: 26861310; PMCID: PMC4783956.
- Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, Watkins PB, Navarro V, Barnhart H, Gu J, Serrano J; United States Drug Induced Liver Injury Network. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology. 2015 Jun;148(7):1340-52.e7. doi: 10.1053/j.gastro.2015.03.006. Epub 2015 Mar 6. PMID: 25754159; PMCID: PMC4446235.
- Francis P, Navarro VJ. Drug-Induced Hepatotoxicity. [Updated 2022 Nov 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557535/
- Muratori L, Lohse AW, Lenzi M. Diagnosis and management of autoimmune hepatitis. BMJ. 2023;380:e070201. doi: 10.1136/bmj-2022-070201.
- Patel R, Mueller M. Alcoholic Liver Disease. [Updated 2023 Jul 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546632/
- Singh A, Koritala T, Jialal I. Unconjugated Hyperbilirubinemia. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549796/
- Tripathi N, Jialal I. Conjugated Hyperbilirubinemia. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562172/
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[^1]: Original PDF page 1: [[L23 Liver Diseases.pdf#page=1|L23 Liver Diseases, p.1]]
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