Implications of Liver Disease to the Oral Health Care Provider

Clinical Presentation and Professional Overview¹

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.

Pathophysiology of Liver Disease

Liver disease must be viewed through a broad lens, specifically distinguishing between the pre-cirrhotic stage and cirrhosis. The liver responds to various inflammatory insults by fibrosing; when this fibrosis becomes severe, the liver is deemed cirrhotic. This condition significantly impairs function and increases the risk of hepatocellular carcinoma.

Physiology and Functions of the Liver

Homeostasis

The liver maintains homeostasis through a multitude of complex roles. When diseased, a shift in homeostasis occurs, which can manifest as systemic disease or contribute to the progression of existing oral conditions.

Storage Functions²

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.
- Albumin: Essential for the transport of substances like unconjugated bilirubin in the blood.
Coagulation Factors: Production of essential clotting factors, excluding a portion of factor VIII.
- In patients with severe liver disease, bleeding risks are a primary concern for dental procedures.
Complement System: Synthesis of components required for the innate immune response.
Bile Formation: Production of bile necessary for digestion and absorption of fats.
- Bilirubin Processing: The liver converts heme-derived toxins into excretable bile.

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.
- The liver is the primary site for drug biotransformation. In cirrhotic patients, the "hepatic reserve" is limited, making them highly susceptible to drug-induced injury.
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.
- In advanced disease (cirrhosis with ascites), patients lose certain immune protections and become highly susceptible to conditions like bacterial peritonitis.

Pathophysiology and Classification of Liver Disease

Progression of Chronic Liver Disease

Stages of Liver Disease Progression³

Precirrhotic Disease: Typically spans a duration of 10–35 years
Hepatitis: Acute or chronic inflammation.
Fibrosis: The liver's scarring response to inflammation.
Cirrhosis: Severe fibrosis leading to impaired function.
- Compensated Cirrhosis: The liver is scarred but can still perform most functions.
- Decompensated Cirrhosis: The liver can no longer compensate, leading to instability and symptoms. .
Compensated Cirrhosis: Typically lasts 10–15 years.
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:

Clinical Concern

Any further insult to the hepatocytes in a cirrhotic patient can trigger acute decompensation or systemic failure.

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
Acute Decompensation: Organ dysfunction with a significant mortality rate.
Acute-on-Chronic Liver Failure: Systemic failure with an even higher mortality rate.

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.

Etiology of Chronic Hepatitis

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 Categories⁴

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.

Alcoholic Liver Disease

Classification of Liver Diseases⁵

Alcoholic liver disease
Nonalcoholic fatty liver disease (NAFLD)
Viral Hepatitis
Autoimmune hepatitis
Drug induced hepatitis / Drug induced liver injury (DILI)

Info

Alcoholic liver disease (ALD) results from hepatocellular injury caused by alcohol consumption exceeding the liver's tolerance.

Histological Stages of Alcoholic Liver Disease

Pathological Progression⁶

Alcoholic fatty liver (Steatosis)

Characterized by fat accumulation in the liver parenchyma.
Often asymptomatic.
If inflammation or necrosis is present, it is termed steatohepatitis.

Steatohepatitis

Fat accumulation accompanied by inflammation and necrosis; also often asymptomatic.

Alcoholic hepatitis

Characterized by active inflammation of the liver cells.
- Symptomatic inflammation (jaundice, nausea, abdominal pain).

Alcoholic cirrhosis

Involves irreversible liver damage and leads to severe clinical complications.

Consumption Guidelines and Standard Drinks

NHMRC Consumption Guidelines⁷

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.

Risk Thresholds for Liver Damage⁸

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.

Clinical Manifestations and Physical Examination

Physical Examination Findings⁹

Note: Patients with liver disease often present with very few clinical signs.

General Appearance
- Jaundice
- Smell of alcohol / fetor hepaticus
- Encephalopathy
- Weight loss
  - Many patients are asymptomatic; it is often a "silent disease."
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
  - Bilateral parotid swelling is a classic sign.
    - Spider naevi (spider angiomas), particularly on the bridge of the nose, face, hands, and legs.
- 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

Practice Implications for Alcohol Use Disorder

Medication Management and Interactions¹⁰

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).

Nonalcoholic Fatty Liver Disease

Common Types of Liver Disease¹¹

Pathogenesis and Spectrum of Disease

Prevalence and Clinical Overview¹²

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.

Management and Surgical Interventions

Clinical Management Strategies¹³

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.

Viral Hepatitis¹⁴

Comparison of Hepatitis Viruses A through E¹⁵

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

Clinical Implications for Dental Practitioners

Occupational Transmission Risks¹⁶

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
It cannot be "cured" due to its episomal DNA structure in the host nucleus, but it can be prevented via vaccine.
Hepatitis C: There is a 20% chance of resolution of acute hepatitis, with an 80% chance of progressing to a chronic state
Hepatitis C can now be cured with direct-acting antivirals.
Even if cured, the risk of liver cancer remains, requiring lifelong monitoring.

Hepatitis C Diagnostic Testing

Diagnostic Methodology¹⁷

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.

Hepatitis B Structure and Serologic Markers

Hepatitis B Virus Structure¹⁸

The Hepatitis B virus structure is characterized by specific serologic targets used for diagnostic testing and monitoring.

Viral Antigens

The virus contains Surface antigens (HBsAg), E antigens (HBeAg), and Core antigens (HBcAg).

Clinical Course and Serology¹⁹

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
Immunity can be from either recovery or vaccination.
Anti-HBc: Indicates any history of infection.
IgM Anti-HBc: Indicates recency of infection; also used for detection during the surface antigen seronegative window.
Acute HBV Infection with Recovery (Typical Serologic Course)
Progression to Chronic HBV Infection (Typical Serologic Course)
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 Patients²⁰

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.

Autoimmune Hepatitis²¹

Epidemiology and Etiology of Autoimmune Hepatitis

Disease Description and Pathogenesis²²

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

Prognosis

Untreated cases of autoimmune hepatitis can lead to death within five years.

Drug Induced Liver Injury²³

Considerations for Cirrhotic Patients²⁴

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.

Pathogenesis and Classification of Hepatotoxicity

Definition and Categorization²⁵

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.

Clinical Management of Drug Induced Liver Injury²⁶

Clinical Presentation²⁷

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.

Identification of specific hepatotoxic drugs is essential for clinical management.

Hepatotoxic Drug Categories and Likelihood

LiverTox Resource and Likelihood Categories²⁸

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

Category A Drugs (> 50 Published Reports)²⁹

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

Jaundice and Bilirubin Metabolism³⁰

Jaundice is a clinical manifestation of elevated bilirubin levels in the blood, resulting in the yellowing of the skin and mucous membranes.

Physiology of Bilirubin Production and Excretion

Bilirubin Production and Initial Processing³¹

The conversion of heme to bilirubin is a two-step process:

Heme to Biliverdin: Heme (derived from erythrocytes) is converted to biliverdin, occurring mainly in the spleen.
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.

Excretion and Metabolism of Conjugated Bilirubin³²

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:

Stool Excretion: It is excreted in the stool as stercobilinogen.
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.

Summary of Hepatic Transformation³³

UNCONJUGATED BILIRUBIN → LIVER → CONJUGATED BILIRUBIN

Causes of Unconjugated Hyperbilirubinemia

Increased Bilirubin Production³⁴

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.
- Gilbert Syndrome: A common, benign hereditary defect in conjugation that causes low-level jaundice.
Crigler-Najjar syndrome.

Causes of Conjugated Hyperbilirubinemia

Extrahepatic Cholestasis³⁵

Biliary Obstruction: Caused by conditions such as primary sclerosing cholangitis or AIDS cholangiopathy.
- Gallstones or duct obstruction.
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 of Clinical Key Points

Medication and Drug Considerations³⁶

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.
Consult the LiverTox database for Category A drugs to assess potential hepatotoxicity.
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.
The liver produces clotting factors; expect prolonged bleeding in advanced disease and consult with the patient's GP or specialist.

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.

Gilbert Syndrome

Gilbert Syndrome is a common, hereditary defect in the conjugation of bilirubin. Patients are generally healthy but may present with mild, intermittent jaundice because they cannot process bilirubin efficiently when the system is stressed. It is considered an "inert" or benign condition.

Unstable or decompensated patients (e.g., those with ascites) should be treated in a hospital dental setting.

References³⁷

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/
LiverTox Database (National Institute of Diabetes and Digestive and Kidney Diseases).

Audio Appendix

Additional Audio Content

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