Liver Cirrhosis

Definition

Liver cirrhosis is not just a disease, but the end-stage anatomical consequence of sustained, chronic liver injury. Think of it as the liver's "scar tissue response" gone too far. It's defined by three key, interconnected pathological hallmarks that you can see under the microscope:

1. Diffuse Hepatic Fibrosis: This isn't just a small scar. It's a widespread deposition of abnormal, dense collagen (predominantly Type I) that forms a spiderweb-like network throughout the liver. This replaces the normal, delicate extracellular matrix.
2. Nodular Regeneration: The surviving hepatocytes, trapped in this fibrous web, attempt to regenerate. However, because the normal scaffolding is destroyed, they form clumps called regenerative nodules. These nodules are not functional liver units (lobules) and lack a central vein and portal triads.
3. Architectural Distortion: The combination of fibrosis and nodules completely disrupts the liver's normal microscopic and macroscopic structure. The organized portal triads and central veins are lost. This is the key difference from simple hepatic fibrosis, where the architecture is preserved.

Reversibility: This is a critical concept. Early cirrhosis, often termed "compensated cirrhosis," may be reversible if the underlying cause is aggressively treated (e.g., curing Hepatitis C, abstinence in alcohol-related disease, chelation in hemochromatosis). However, advanced cirrhosis with extensive nodularity and portal hypertension becomes irreversible. At this stage, the only curative treatment is liver transplantation.

Epidemiology and Risk Factors

Globally, the leading causes of cirrhosis are Hepatitis B (HBV), Hepatitis C (HCV), and Alcohol-Related Liver Disease (ALD). However, the epidemiology in Hong Kong has its own distinct profile, largely driven by the high prevalence of HBV.

In Hong Kong, Chronic Hepatitis B is the overwhelming cause of liver cirrhosis. The carrier rate in the general population is approximately 7-8%, a legacy of pre-vaccination era vertical transmission. A significant proportion of these carriers progress to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).

Global and Local Risk Factors

• Viral Hepatitis: Hepatitis B virus (HBV) and Hepatitis C virus (HCV). Chronic infection leads to persistent immune-mediated inflammation, hepatocyte death, and eventually fibrosis. HBV also has direct oncogenic properties (via the HBx protein), which can promote carcinogenesis even before cirrhosis develops.
• Alcohol: Chronic, excessive alcohol consumption is a major cause. Risk is dose-dependent (typically >60-80g/day for men, >20g/day for women over 10+ years). Ethanol metabolism generates toxic metabolites (acetaldehyde) and causes oxidative stress, leading to steatosis, hepatitis, and fibrosis.
• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): This is the new terminology (as of 2023) replacing NAFLD. It's tightly linked to insulin resistance, obesity, type 2 diabetes, and dyslipidemia. A subset progresses to MASH (metabolic dysfunction-associated steatohepatitis), which can lead to cirrhosis.
• Autoimmune & Biliary Diseases:
  • Autoimmune Hepatitis: Immune system attacks hepatocytes.
  • Primary Biliary Cholangitis (PBC): Immune-mediated destruction of small intrahepatic bile ducts, leading to cholestasis and cirrhosis. Strong female predominance (F:M ~9:1) and association with other autoimmune conditions like Sjögren's syndrome and thyroiditis.
  • Primary Sclerosing Cholangitis (PSC): Inflammation and fibrosis of both intra- and extra-hepatic bile ducts, creating a "beaded" appearance on imaging. Strongly associated with Inflammatory Bowel Disease (IBD), especially Ulcerative Colitis.
• Genetic/Metabolic Disorders:
  • Hemochromatosis (HFE gene): Autosomal recessive disorder of iron overload. Excess iron deposits in hepatocytes, catalyzing free radical formation and fibrosis.
  • Wilson's Disease (ATP7B gene): Autosomal recessive disorder of copper metabolism. Copper accumulation in the liver is directly toxic.
  • Alpha-1 Antitrypsin Deficiency: Mutant protein (PiZZ) polymerizes and gets trapped in hepatocytes, causing injury.
• Vascular: Chronic right-sided heart failure (e.g., severe tricuspid regurgitation, constrictive pericarditis) leads to congestive hepatopathy. Sustained high pressure in the hepatic veins backs up into the sinusoids, causing centrilobular congestion, atrophy, and fibrosis ("nutmeg liver").
• Drugs/Toxins: Certain medications are notorious for causing chronic liver injury that can progress to cirrhosis, e.g., methotrexate (cumulative dose-related), amiodarone (can cause a steatohepatitis-like picture), and high-dose vitamin A.

Anatomy and Function (Relevance to Cirrhosis)

To understand why cirrhosis causes its myriad complications, you must first understand the liver's dual blood supply and its microarchitecture.

1. Vascular Anatomy: The Dual Supply

• Portal Vein (75% of blood flow): Brings nutrient-rich, deoxygenated blood from the intestines, spleen, and stomach to the liver. It also carries gut-derived bacterial products and toxins.
• Hepatic Artery (25% of blood flow): Brings oxygenated blood from the celiac trunk.

These two vessels branch together into the liver at the portal triads (portal vein, hepatic artery, bile duct). Blood from both sources mixes in the hepatic sinusoids (the liver's capillaries), bathes the hepatocytes, and then drains into the central vein. Central veins coalesce into hepatic veins, which drain into the Inferior Vena Cava (IVC).

2. The Functional Unit: The Hepatic Lobule vs. The Acinus

• Classic Lobule (Hexagonal): Centered on the central vein. Blood flows from the periphery (portal triads) towards the center.
• Rappaport's Liver Acinus (More Physiologically Relevant): Zones hepatocytes based on their oxygen and nutrient supply.
  • Zone 1 (Periportal): Closest to the portal triad. Gets the best oxygen/nutrient supply. Rich in mitochondria for oxidative metabolism. Site of urea and glutamine synthesis, bile acid-independent bile flow, and cholesterol synthesis.
  • Zone 2 (Midzonal): Intermediate.
  • Zone 3 (Pericentral/Centrilobular): Surrounds the central vein. Most vulnerable to injury from ischemia (low O2) and toxic metabolites (e.g., from alcohol, acetaminophen). Site of cytochrome P450 detoxification, glycolysis, lipogenesis, and bile acid-dependent bile flow.

3. The Sinusoidal Lining & Space of Disse

The sinusoid is a unique, fenestrated (has holes) capillary. Lining it are:

• Liver Sinusoidal Endothelial Cells (LSECs): These are highly fenestrated, allowing easy passage of small molecules from blood to hepatocytes.
• Hepatic Stellate Cells (HSCs): These live in the Space of Disse (the space between the sinusoid and hepatocytes). In health, they store vitamin A. In injury, they are the master regulators of fibrosis. They become "activated," transforming into myofibroblast-like cells that proliferate and produce massive amounts of collagen (Types I and III), laying down the fibrous scar.

4. Key Functions Affected in Cirrhosis

• Synthesis: Albumin, coagulation factors (except Factor VIII), cholesterol, carrier proteins.
• Metabolism: Gluconeogenesis, glycogen storage, ammonia → urea (detoxification).
• Detoxification & Excretion: Bilirubin conjugation, drug metabolism, bile acid synthesis and secretion.
• Immune & Filter Function: Kupffer cells (liver macrophages) clear bacteria and endotoxins from portal blood.

Etiology and Pathophysiology (Focus on Hong Kong)

The journey from a healthy liver to cirrhosis follows a common final pathway, regardless of the initial insult: chronic injury → inflammation → activation of stellate cells → fibrosis → architectural distortion.

Let's break down the dominant etiologies in HK:

1. Hepatitis B Virus (HBV) – The Major Player

• Mechanism: Chronic HBV infection leads to a persistent, immune-mediated cytotoxic T-cell attack on infected hepatocytes. This causes recurrent cycles of hepatocyte necrosis and regeneration. Over decades, this sustained injury activates HSCs, leading to fibrosis.
• Direct Oncogenic Effect: HBV DNA integrates into the host genome. The viral protein HBx dysregulates cellular signaling pathways (e.g., p53 tumor suppression, Wnt/β-catenin), promoting genetic instability and carcinogenesis. This is why HBV-related HCC can occur in a non-cirrhotic liver (in about 20% of cases), unlike HCV where HCC almost always arises on a background of cirrhosis.
• Epidemiology in HK: A chronic HBV carrier has a 20-30% lifetime risk of developing cirrhosis. The progression is slow, usually taking 10-15 years of chronic hepatitis.

2. Hepatitis C Virus (HCV)

• Mechanism: Also causes chronic immune-mediated injury. HCV does not integrate into DNA; its carcinogenic effect is almost entirely mediated through the chronic inflammatory milieu of cirrhosis. Therefore, HCV-related HCC occurs almost exclusively in the setting of established cirrhosis.
• HK Context: Less common than HBV, but important.

3. Alcohol-Related Liver Disease (ALD)

• Pathogenesis: A classic example of toxic injury.
  1. Metabolism: Alcohol dehydrogenase (ADH) in hepatocytes converts ethanol to acetaldehyde, a highly toxic and reactive molecule.
  2. Acetaldehyde Damage: Binds to proteins and DNA, forming adducts that promote inflammation, impair mitochondrial function, and generate oxidative stress.
  3. Oxidative Stress: Chronic alcohol use induces cytochrome P450 2E1 (CYP2E1), which metabolizes ethanol but also produces reactive oxygen species (ROS).
  4. Inflammation: ROS and acetaldehyde damage hepatocytes, release damage-associated molecular patterns (DAMPs), and activate Kupffer cells. This leads to release of pro-inflammatory cytokines (e.g., TNF-α, IL-6).
  5. Stellate Cell Activation: The cytokine storm and damaged hepatocytes activate HSCs, driving fibrosis. Alcoholic hepatitis is an acute-on-chronic flare of intense inflammation and hepatocyte ballooning that accelerates the path to cirrhosis.

4. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) / Steatohepatitis (MASH)

• The "Two-Hit" Hypothesis (Simplified):
  1. First Hit – Steatosis: Insulin resistance leads to increased free fatty acid delivery to the liver and increased de novo lipogenesis. The liver becomes fatty (steatosis).
  2. Second Hit – Inflammation: The fatty liver is vulnerable. Lipid peroxidation in hepatocytes generates ROS and lipid peroxides. This causes cellular stress, releases cytokines, and activates HSCs, leading to steatohepatitis (MASH) and fibrosis.
• Why it matters in HK: With rising obesity and diabetes, MASLD is now the fastest-growing cause of liver disease worldwide and in Hong Kong.

5. Primary Biliary Cholangitis (PBC)

• Pathogenesis: An autoimmune disorder targeting the mitochondrial pyruvate dehydrogenase complex (PDC-E2) on the inner lining of small intrahepatic bile duct epithelial cells.
• Consequence: CD4+ and CD8+ T-cells destroy these small ducts (non-suppurative destructive cholangitis). Bile cannot flow out (cholestasis). Retained bile acids are toxic to surrounding hepatocytes, causing a "bile infarct" and perpetuating inflammation and fibrosis in the portal tracts, eventually leading to cirrhosis.
• Classic Serology: Anti-Mitochondrial Antibodies (AMA) are present in ~95% of cases.

Classification of Cirrhosis

Cirrhosis can be classified in several useful ways:

1. By Morphology (Macroscopic Appearance)

• Micronodular: Nodules are small and uniform, typically < 3 mm in diameter. Classic of alcoholic cirrhosis and hemochromatosis in early stages.
• Macronodular: Nodules are large and variable in size (>3 mm), separated by broad fibrous bands. Typical of viral hepatitis-related cirrhosis.
• Mixed: Features of both.

2. By Etiology

As detailed above (Viral, Alcoholic, Metabolic, Autoimmune, etc.). This is the most clinically relevant classification as it guides treatment.

3. By Clinical Stage (Compensated vs. Decompensated)

This is the most important classification for prognosis and management.

• Compensated Cirrhosis: The liver is scarred but is still able to perform its essential functions. The patient has no overt symptoms or complications. Survival is measured in years to decades.
• Decompensated Cirrhosis: The liver's synthetic and detoxifying functions fail, and the complications of portal hypertension manifest. Defined by the occurrence of any of the following:
  1. Ascites (most common first decompensating event)
  2. Variceal Hemorrhage
  3. Hepatic Encephalopathy
  4. Jaundice due to liver failure Survival drops dramatically to months to a few years without transplant.

4. By Severity (Child-Pugh & MELD Scores)

These scores quantify the severity of liver dysfunction and are critical for prognostication and transplant listing.

• Child-Pugh Score: Uses 5 clinical/lab parameters (Albumin, Bilirubin, INR, Ascites, Encephalopathy). Classes A, B, C.
• Model for End-Stage Liver Disease (MELD) Score: A more objective, continuous score calculated from INR, Bilirubin, and Creatinine (and Sodium for MELD-Na). Used to prioritize patients for liver transplantation.

Clinical Features

The clinical presentation of cirrhosis is incredibly variable, from completely asymptomatic (compensated) to critically ill with multi-organ failure (decompensated). All features can be traced back to two fundamental pathophysiological derangements: 1) Hepatocellular Dysfunction/Failure and 2) Portal Hypertension.

Symptoms

A. Constitutional Symptoms (Non-Specific)

• Fatigue, Malaise, Weakness: Extremely common. Likely multifactorial: chronic inflammation, altered neuroendocrine signaling, and possibly low-grade cerebral edema.
• Anorexia, Weight Loss, Muscle Wasting (Sarcopenia): Due to:
  • Chronic inflammation (cytokines like TNF-α are catabolic).
  • Altered metabolism and poor nutrient intake.
  • Sarcopenia (loss of muscle mass) is a major predictor of poor outcomes in cirrhosis, independent of liver function.
• Muscle Cramps: Painful, especially at night. Related to electrolyte imbalances, reduced effective circulatory volume, and peripheral neuropathy.

B. Symptoms of Hepatocellular Dysfunction

• Jaundice: Yellowing of skin/sclera. Due to the liver's inability to conjugate and excrete bilirubin. Mechanism: As functional hepatocyte mass declines, conjugated hyperbilirubinemia predominates.
• Dark Urine: Conjugated bilirubin is water-soluble and excreted in urine.
• Pruritus (Itching): Particularly prominent in cholestatic liver diseases (PBC, PSC). Caused by retained bile acids and other pruritogens (like lysophosphatidic acid) depositing in the skin.
• Easy Bruising & Bleeding Tendency:
  • Synthetic Failure: Reduced production of clotting factors (II, VII, IX, X, V, XI, XIII, fibrinogen). Factor VII has the shortest half-life (~6 hrs), so an isolated prolonged PT/INR is often the earliest lab sign of synthetic dysfunction.
  • Vitamin K Deficiency: Malabsorption of fat-soluble vitamins (A, D, E, K) due to reduced bile salt secretion, which is necessary for their absorption. This further impairs synthesis of Factors II, VII, IX, X.
  • Thrombocytopenia: From portal hypertension-induced splenomegaly and hypersplenism (platelet sequestration).
• Endocrine Disturbances:
  • In Men: Hypogonadism (loss of libido, impotence, testicular atrophy), Gynecomastia, and a female pattern of hair distribution.
    • Why? The liver fails to metabolize estrogens (increased estradiol) and adrenal androgens (like androstenedione, which is peripherally converted to estrone). There's also suppression of gonadotropin-releasing hormone (GnRH).
  • In Women: Menstrual irregularities (oligomenorrhea, amenorrhea), infertility.

C. Symptoms of Portal Hypertension & Its Complications

• Abdominal Distension: From ascites – the accumulation of free fluid in the peritoneal cavity. Patients feel full, bloated, and their clothes get tight.
• Lower Limb Edema: Due to hypoalbuminemia (reduced oncotic pressure) and portal hypertension (increased hydrostatic pressure).
• Hematemesis/Melena: Painless, large volume vomiting of blood or black tarry stools is the classic presentation of acute variceal hemorrhage from ruptured esophageal or gastric varices. A life-threatening emergency.
• Confusion, Altered Mental Status, Sleep Disturbance: Symptoms of hepatic encephalopathy. Ranges from subtle sleep reversal and poor concentration (minimal HE) to coma (overt HE). Caused by the failure of the liver to detoxify gut-derived neurotoxins, especially ammonia.

Signs (Physical Examination)

General Examination (Stigmata of Chronic Liver Disease)

These are clues that hint at long-standing liver dysfunction.

• Jaundice: Scleral icterus, yellow skin.
• Excoriations: Scratch marks from pruritus.
• Spider Angiomata (Nevi): Central arteriole with radiating small vessels, found on the face, neck, and upper trunk. Due to increased estrogen causing vasodilation. Not specific but highly suggestive.
• Palmar Erythema: Reddening of the thenar and hypothenar eminences. Also estrogen-mediated vasodilation.
• Dupuytren's Contracture: Thickening and shortening of palmar fascia, causing finger flexion. Classically associated with alcoholism.
• Xanthelasma: Yellow cholesterol deposits around eyes. Seen in cholestatic diseases like PBC.
• Parotid Enlargement: Associated with alcoholic liver disease.
• Gynecomastia & Testicular Atrophy: As described above.
• Sarcopenia/Muscle Wasting: Prominent clavicles, temporal wasting.

Abdominal Examination

• Inspection:
  • Distension: From ascites.
  • Caput Medusae: Dilated veins radiating from the umbilicus. Rare but pathognomonic for portal hypertension. Due to recanalization of the umbilical vein (part of the falciform ligament) shunting blood to the abdominal wall veins.
  • Visible peristalsis/hernias: Due to increased intra-abdominal pressure from ascites (umbilical, inguinal, incisional).
• Palpation:
  • Liver: Can be enlarged, normal-sized, or shrunken.
    • Viral cirrhosis (HBV/HCV) often leads to a small, firm, nodular, non-tender liver.
    • Alcoholic and cardiac cirrhosis may present with a large, firm liver.
  • Spleen: Splenomegaly is a cardinal sign of portal hypertension. The enlarged spleen sequesters platelets and white cells, contributing to thrombocytopenia and leukopenia (hypersplenism).
• Percussion:
  • Shifting Dullness or Fluid Thrill: To confirm the presence of ascites.
• Auscultation:
  • Bruit over the liver: Uncommon, but if present, think of Hepatocellular Carcinoma (HCC) (tumor vascularity) or alcoholic hepatitis.

Other Systemic Signs

• Fetor Hepaticus: A sweet, musty breath odor due to exhaled volatile sulfur compounds (e.g., mercaptans) from gut bacteria, which the failing liver cannot metabolize.
• Asterixis ("Liver Flap"): A negative myoclonus – a brief, involuntary loss of postural tone causing a flapping tremor of the wrists when extended. A classic sign of hepatic encephalopathy. Caused by disrupted neuronal metabolism in the brain.
• Peripheral Edema: Pitting edema in the lower limbs.

Active Recall - Liver Cirrhosis Fundamentals

1. What are the three definitive pathological features that distinguish cirrhosis from simple hepatic fibrosis?

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1. Diffuse hepatic fibrosis (bridging fibrosis). 2. Formation of regenerative nodules. 3. Distortion of the normal hepatic architecture.

2. In Hong Kong, what is the single most important etiological agent for liver cirrhosis, and what percentage of cases does it account for?

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Chronic Hepatitis B Virus (HBV) infection. It accounts for over 90% of cirrhosis cases in Hong Kong.

3. Explain why a patient with alcoholic liver disease might develop both micronodular cirrhosis and gynecomastia, linking the pathophysiology.

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Chronic alcohol toxicity causes hepatocyte injury and necrosis, activating hepatic stellate cells leading to diffuse fibrosis and micronodular regeneration. Concurrently, the damaged liver fails to metabolize estrogens, leading to hyperestrogenemia. This causes vasodilation (spider nevi) and stimulates breast glandular tissue in males, resulting in gynecomastia.

4. What is the significance of the Hepatic Venous Pressure Gradient (HVPG)? What values define portal hypertension and clinically significant portal hypertension?

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HVPG is the difference between wedged and free hepatic venous pressure, reflecting sinusoidal pressure. Normal HVPG is 1-5 mmHg. Portal hypertension is HVPG ≥6 mmHg. Clinically significant portal hypertension (risk of varices and ascites) is HVPG ≥10 mmHg.

5. A patient with known cirrhosis presents with new-onset confusion and a flapping tremor of the wrists. Name this syndrome and describe its primary pathophysiological basis.

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Hepatic encephalopathy. The primary basis is the failure of the cirrhotic liver to detoxify gut-derived nitrogenous toxins, especially ammonia, which leads to astrocyte dysfunction and cerebral edema.

6. List four clinical events that define the transition from compensated to decompensated cirrhosis.

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1. Development of ascites. 2. Variceal hemorrhage. 3. Overt hepatic encephalopathy. 4. Jaundice due to progressive liver failure.

References

^[1] Senior notes: felixlai.md (Liver Cirrhosis - Overview, Etiology, Clinical manifestation, Pathogenesis, Diagnosis, Complication) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma - Overview, Risk factors; Gynaecomastia) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (HCC Aetiology, Pathology, Clinical Presentation) ^[4] Lecture slides: HCC and Gallstone acute cholangitis_Prof TT Cheung.pdf (HCC Aetiology)

Differential Diagnosis for Liver Cirrhosis

When a patient presents with signs and symptoms suggestive of liver cirrhosis, the clinician's mind must navigate a broad landscape of potential conditions. The goal is to confirm cirrhosis as the diagnosis while simultaneously identifying its underlying cause. This process is a two-pronged diagnostic challenge: first, to distinguish cirrhosis from other conditions that mimic its clinical presentation, and second, to pinpoint the specific etiology of the cirrhosis itself.

The classic triad of portal hypertension, hepatocellular dysfunction, and specific stigmata is highly suggestive but not exclusive to cirrhosis. Other diseases can masquerade as cirrhosis, and some can even co-exist with it.

Here’s a systematic approach to the differential diagnosis, structured from the most common to the less common, always anchored in the pathophysiology of the presenting signs.

1. Non-Cirrhotic Causes of Portal Hypertension & Chronic Liver Disease

These conditions can produce portal hypertension, splenomegaly, and even variceal bleeding, but the liver architecture is preserved.

• Non-Cirrhotic Portal Hypertension (e.g., Idiopathic Portal Hypertension, Nodular Regenerative Hyperplasia): The liver develops regenerative nodules without significant fibrosis, leading to increased intrahepatic resistance. Patients present with varices and splenomegaly but have relatively preserved liver synthetic function. It is a key differential in patients with portal hypertension but near-normal liver enzymes and no obvious cause of cirrhosis ^[1].
• Pre-Sinusoidal Portal Hypertension:
  • Portal Vein Thrombosis (PVT): Blockage of the main portal vein increases pressure upstream without intrinsic liver disease. Common in hypercoagulable states, abdominal sepsis, or after umbilical vein catheterization. Presents with acute variceal bleeding in a patient with a normal-sized, smooth liver.
  • Schistosomiasis: A major global cause of non-cirrhotic portal fibrosis. Schistosoma eggs lodge in portal venules, triggering a granulomatous inflammatory reaction and presinusoidal fibrosis ("pipe-stem fibrosis"). Endemic in some regions but rare in Hong Kong.
• Post-Sinusoidal Portal Hypertension:
  • Budd-Chiari Syndrome: Thrombosis of the hepatic veins or Inferior Vena Cava (IVC). This leads to hepatic outflow obstruction, centrilobular congestion, and eventually fibrosis. Patients present with painful hepatomegaly, ascites (often refractory), and rapid progression to liver failure. It is a crucial differential in a young patient with acute-onset ascites and hepatomegaly ^[2].
  • Congestive Hepatopathy (Cardiac Cirrhosis): Chronic right-sided heart failure (e.g., severe tricuspid regurgitation, constrictive pericarditis) causes sustained high pressure in the hepatic veins. This results in chronic passive congestion, centrilobular hepatocyte atrophy, and fibrosis, eventually leading to a "nutmeg liver" and cirrhosis. The liver is often firm, smooth, and pulsatile. Key clues are elevated jugular venous pressure (JVP) and other signs of heart failure ^[2].

2. Other Chronic Inflammatory & Infiltrative Liver Diseases (Without Established Cirrhosis)

These conditions cause hepatomegaly, abnormal LFTs, and systemic symptoms but may not have yet progressed to the architectural distortion of cirrhosis.

• Chronic Viral Hepatitis (B, C, D): Active inflammation can cause hepatomegaly, fatigue, and jaundice. The liver may be tender. The absence of stigmata of chronic liver disease and portal hypertension suggests the disease is still in the hepatitis stage rather than cirrhotic. This is a pre-cirrhotic stage of the same disease ^[2].
• Autoimmune Hepatitis (AIH): An immune-mediated attack on hepatocytes, typically in young to middle-aged women. Can present with acute hepatitis or insidious onset of fatigue and jaundice. May progress to cirrhosis if untreated. Diagnosed by high serum IgG, positive autoantibodies (ANA, ASMA, anti-LKM1), and characteristic histology (interface hepatitis, plasma cell infiltrate) ^[2].
• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): This encompasses simple steatosis and its inflammatory form, MASH. Patients are often asymptomatic but may have mild hepatomegaly and elevated ALT/AST. Severe hepatomegaly with a soft, smooth edge can be a clue, especially in obese or diabetic patients. Progression to cirrhosis is possible but takes years ^[2].
• Infiltrative Disorders:
  • Amyloidosis: Protein deposits in the liver sinusoids cause massive, rock-hard hepatomegaly. LFTs are often surprisingly normal until late stages. Look for other systemic signs (macroglossia, periorbital purpura, renal disease).
  • Granulomatous Hepatitis: Sarcoidosis, TB, fungal infections. Causes persistent hepatomegaly and mild LFT derangement. Diagnosis often requires liver biopsy showing non-caseating (sarcoid) or caseating (TB) granulomas.

3. Malignant & Benign Space-Occupying Lesions

These can cause hepatomegaly, RUQ pain, and constitutional symptoms, potentially mimicking decompensated cirrhosis or HCC.

• Hepatocellular Carcinoma (HCC): This is both a complication of cirrhosis and a differential for new liver masses. It is the commonest primary liver cancer (80%) and frequently associated with cirrhosis (80% in Hong Kong) ^[3]. A new-onset hepatic bruit, rapid clinical deterioration, or a disproportionate rise in AFP in a cirrhotic patient should raise suspicion. HCC can also arise in non-cirrhotic livers, particularly with HBV ^[2].
• Cholangiocarcinoma: Adenocarcinoma of the bile ducts. Perihilar tumors (Klatskin tumors) present with obstructive jaundice early. Intrahepatic tumors can present as a liver mass without jaundice, mimicking HCC. Risk factors include PSC, RPC, and liver flukes (Clonorchis sinensis in HK) ^[4]. It is not typically associated with high AFP.
• Liver Metastases: Metastatic disease is far more common than primary liver cancer. Carcinomas from the colon, stomach, pancreas, breast, and lung are common culprits. The liver may be enlarged, nodular, and hard. Imaging typically shows multiple, hypovascular lesions, in contrast to the hypervascular profile of HCC ^[1][2].
• Benign Liver Tumours:
  • Hemangioma: The most common benign liver tumor ^[2]. Usually asymptomatic and found incidentally. Giant hemangiomas can cause abdominal discomfort. It is hyperechoic on USG and shows characteristic peripheral nodular enhancement on CT with slow fill-in.
  • Focal Nodular Hyperplasia (FNH): A benign hyperplastic response to a congenital vascular malformation. Common in young women. It is a usually solitary lesion with a central stellate scar on imaging. It has no malignant potential and does not rupture ^[2].
  • Hepatic Adenoma: A benign neoplasm strongly associated with oral contraceptive use. Presents as a usually solitary RUQ mass. The major risk is spontaneous rupture and hemorrhage, and it carries a small risk of malignant transformation to HCC ^[2].

4. Primary Biliary & Cholestatic Diseases

These cause pruritus, jaundice, and hepatomegaly, but the primary pathology is in the bile ducts.

• Primary Biliary Cholangitis (PBC): An autoimmune disorder destroying small intrahepatic bile ducts. Presents with pruritus and fatigue, often in middle-aged women. Key diagnosis: elevated ALP + positive Anti-Mitochondrial Antibodies (AMA). Can progress to biliary cirrhosis ^[5].
• Primary Sclerosing Cholangitis (PSC): Inflammation and fibrosis of intra- and extra-hepatic bile ducts, leading to a "beaded" appearance on cholangiography. Strongly associated with Inflammatory Bowel Disease (especially Ulcerative Colitis). Presents with pruritus, jaundice, and recurrent cholangitis. A major risk factor for cholangiocarcinoma ^[6].

5. Systemic & Extra-Hepatic Conditions Mimicking Cirrhosis Complications

• Causes of Ascites:
  • Heart Failure: Causes transudative ascites via increased hepatic sinusoidal pressure (congestive hepatopathy) and systemic venous pressure. Differentiated by elevated JVP, cardiomegaly, and peripheral edema.
  • Nephrotic Syndrome: Severe hypoalbuminemia leads to reduced oncotic pressure and generalized edema, including ascites. Urinalysis shows massive proteinuria.
  • Peritoneal Carcinomatosis: Metastatic seeding of the peritoneum (e.g., from ovarian, gastric, colon cancer) causes exudative, often bloody ascites. Fluid cytology is diagnostic.
  • Tuberculous Peritonitis: Causes exudative ascites with high lymphocyte count. Patients often have fever, night sweats, and may have evidence of TB elsewhere.
• Causes of Upper GI Bleeding (mimicking variceal hemorrhage): Peptic ulcer disease, gastritis, Mallory-Weiss tear, and gastric cancer can all present with hematemesis. In a patient without known liver disease, these are more common than varices ^[7].

6. Genetic & Metabolic Disorders (Rare but Important)

These are specific etiologies of cirrhosis that must be identified due to targeted treatments.

• Hemochromatosis: Iron overload leads to progressive fibrosis. Look for triad: cirrhosis, diabetes mellitus ("bronze diabetes"), and skin pigmentation. Diagnosed with high transferrin saturation and ferritin, confirmed by genetic testing (HFE gene) or liver biopsy with iron quantification ^[2].
• Wilson's Disease: Copper accumulation. Can present as acute hepatitis, chronic liver disease, or neurological symptoms (parkinsonism, psychiatric). Keys: Kayser-Fleischer rings (on slit-lamp exam), low serum ceruloplasmin, high urinary copper ^[2].
• Alpha-1 Antitrypsin Deficiency: Mutant protein (PiZZ) polymerizes in hepatocytes. Can present with neonatal cholestasis, childhood cirrhosis, or emphysema in adults. Diagnosed by low serum A1AT level and phenotype/genotype confirmation ^[2].

The following Mermaid diagram summarizes the clinical approach to differentiating the causes of a patient presenting with signs of chronic liver disease and portal hypertension.

Active Recall - Differential Diagnosis

1. A 45-year-old man with known HBV carrier status presents with abdominal distension and mild jaundice. Ultrasound shows a shrunken, nodular liver, massive ascites, and splenomegaly. What is the most likely diagnosis, and what is the single most important differential diagnosis you must actively exclude?

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Most likely: Decompensated liver cirrhosis secondary to chronic Hepatitis B. The crucial differential to exclude is Hepatocellular Carcinoma (HCC), which commonly complicates HBV cirrhosis and can present with similar features. An AFP level and contrast-enhanced imaging (triphasic CT/MRI) are mandatory.

2. A 60-year-old woman presents with progressive, painless jaundice and severe pruritus. LFT shows a cholestatic pattern (markedly elevated ALP). Abdominal USG shows no biliary dilation. Which two autoimmune liver diseases are highest on your differential list, and what is the key serological test for each?

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Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). For PBC, check Anti-Mitochondrial Antibodies (AMA). For PSC, check p-ANCA and perform an MRCP to look for characteristic biliary stricturing and dilation.

3. A patient presents with ascites and splenomegaly but has near-normal liver enzymes and synthetic function (normal albumin, INR). What category of conditions should you suspect, and name two specific examples.

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Suspect Non-Cirrhotic Portal Hypertension. Two examples are: 1) Portal Vein Thrombosis, and 2) Idiopathic Portal Hypertension / Nodular Regenerative Hyperplasia.

4. What is the key imaging feature on a triphasic CT scan that differentiates a typical HCC from a liver metastasis?

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HCC is typically hypervascular, showing strong enhancement in the arterial phase followed by 'washout' (becoming hypodense) in the portal venous/delayed phase. Metastases are typically hypovascular and do not show this arterial enhancement/washout pattern.

5. A patient with a history of ulcerative colitis develops jaundice and recurrent episodes of fever with chills. What hepatobiliary condition is strongly associated with their underlying disease, and what is its major long-term risk?

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Primary Sclerosing Cholangitis (PSC) is strongly associated with Ulcerative Colitis. Its major long-term risk is the development of Cholangiocarcinoma.

References

^[1] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (Hepatomegaly – Differential Diagnosis) ^[2] Senior notes: felixlai.md (Causes of liver cirrhosis, Differential diagnosis of hepatomegaly and HCC) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (HCC Aetiology, Pathology) ^[4] Senior notes: felixlai.md (Cholangiocarcinoma etiology and clinical features) ^[5] Senior notes: felixlai.md (Primary biliary cholangitis - Overview, Clinical manifestations) ^[6] Senior notes: felixlai.md (Primary sclerosing cholangitis - Overview, Associated conditions) ^[7] Senior notes: felixlai.md (Differential diagnosis of upper GI bleeding)

Diagnostic Criteria, Algorithm, and Investigations for Liver Cirrhosis

The diagnosis of cirrhosis is not made by a single test, but rather by synthesizing evidence from the clinical presentation, blood tests, imaging, and sometimes histology. The goals are twofold: 1) To confirm the presence of cirrhosis and assess its severity, and 2) To identify the underlying etiology, as this directly determines management.

Diagnostic Criteria: A Composite Picture

There is no single "diagnostic criteria" checklist for cirrhosis itself. Instead, diagnosis is based on a combination of findings. For compensated cirrhosis (often asymptomatic), the diagnosis may be subtle and rely more on imaging or biopsy. For decompensated cirrhosis, the presence of clear complications (ascites, variceal hemorrhage, hepatic encephalopathy) in the right clinical context is often sufficient.

However, for specific diseases causing cirrhosis, there are established criteria:

• Primary Biliary Cholangitis (PBC): Diagnosis requires at least 2 of the following: 1) ALP ≥ 1.5x ULN, 2) Positive AMA at titer ≥1:40, and 3) Histologic evidence of non-suppurative destructive cholangitis ^[1][10].
• Hepatocellular Carcinoma (HCC): In a cirrhotic liver, a liver lesion >1 cm with the typical vascular pattern on dynamic imaging (arterial hyperenhancement and venous/delayed phase washout) is diagnostic without the need for biopsy ^[8][11].

The functional severity of cirrhosis is formally classified using the Child-Pugh Score (which grades from A to C) and quantified by the Model for End-Stage Liver Disease (MELD) score, critical for transplant prioritization.

Diagnostic Algorithm: A Stepwise Approach

When cirrhosis is suspected, follow a logical, tiered investigation strategy. The following algorithm outlines the pathway from initial suspicion to confirmation and etiological diagnosis.

Investigation Modalities and Key Findings

1. Blood Tests: The Functional and Etiological Clues

Blood tests assess the liver's synthetic and metabolic function and point to the cause.

A. Complete Blood Count (CBC) & Clotting Profile

• Thrombocytopenia: A common finding. Caused by: 1) Portal hypertension-induced splenomegaly and hypersplenism (platelet sequestration), and 2) Decreased hepatic production of thrombopoietin ^[3].
• Leukopenia: Also due to hypersplenism.
• Anemia: Multifactorial: chronic disease, gastrointestinal blood loss (varices, gastropathy), nutritional deficiencies (folate in alcoholics), and direct alcohol toxicity.
• Prolonged PT/INR: Reflects impaired synthesis of vitamin K-dependent clotting factors (II, VII, IX, X). Factor VII has the shortest half-life (~6 hours), so an isolated prolonged PT/INR is often the earliest lab sign of synthetic dysfunction ^[3]. It can also be due to vitamin K malabsorption from cholestasis.

B. Liver Function Tests (LFTs) & Biochemistry

• Bilirubin: May be normal in compensation. A rising bilirubin indicates worsening liver function or superimposed events (e.g., alcoholic hepatitis, cholangitis).
• Aminotransferases (AST, ALT): Often only mildly elevated. A characteristic AST:ALT ratio >1 (often ~2:1) is suggestive of cirrhosis, especially alcoholic etiology. Why? AST is mitochondrial and is released with more severe cell injury; ALT is cytosolic. In advanced fibrosis, ALT production may be diminished.
• Alkaline Phosphatase (ALP) & GGT: Mild elevations are common. Marked elevation (e.g., >3x ULN) suggests a cholestatic component (e.g., PBC, PSC, biliary obstruction) ^[4]. GGT is particularly sensitive to alcohol use.
• Albumin: Hypoalbuminemia is a key marker of chronic synthetic failure (albumin half-life ~20 days). It contributes to peripheral edema and ascites formation by lowering plasma oncotic pressure.
• Globulins: Polyclonal hypergammaglobulinemia is common, leading to a reversed A:G ratio. Mechanism: Portosystemic shunting allows gut-derived antigens to bypass the liver's Kupffer cells, leading to sustained B-cell stimulation in the spleen and lymph nodes ^[3][4].
• Renal Function & Electrolytes: Hyponatremia is common due to non-osmotic ADH release from effective arterial hypovolemia. Rising creatinine may indicate hepatorenal syndrome.

C. Etiology-Specific Serology & Markers

• Viral Hepatitis: HBsAg, Anti-HCV. In HBV, check HBeAg/Ab and HBV DNA. In HCV, check HCV RNA. In Hong Kong, Hepatitis B serology is the most critical test ^[1][2].
• Autoimmune: ANA (Autoimmune Hepatitis), AMA (PBC), p-ANCA (PSC).
• Metabolic: Ferritin, Transferrin Saturation (Hemochromatosis), Ceruloplasmin (Wilson's), Alpha-1 Antitrypsin level and phenotype.
• Tumour Marker: Alpha-fetoprotein (AFP). Used for HCC screening. >400 ng/mL is highly suggestive of HCC, but levels can be elevated in active hepatitis and regeneration. 30% of HCC patients have normal AFP ^[9][11].
• Others: IgG4 (for IgG4-related disease mimicking PSC), CA 19-9 (cholangiocarcinoma).

2. Imaging: Visualizing Structure and Consequences

A. Abdominal Ultrasound (USG) – First-Line Imaging

• Findings of Cirrhosis: Surface nodularity, coarse heterogeneous echotexture, atrophy of the right lobe with hypertrophy of the caudate/left lobe ^[5].
• Findings of Portal Hypertension: Splenomegaly, ascites, collateral vessels (e.g., recanalized umbilical vein), portal vein dilatation (>13mm), and reduced/ reversed portal vein flow ^[5].
• Additional Role: Screening for HCC (any solid nodule >1 cm needs further investigation) and detecting portal vein thrombosis.

B. Transient Elastography (FibroScan)

• A non-invasive method to estimate liver stiffness, correlating with fibrosis stage. It uses a shear wave to measure propagation speed; stiffer (fibrotic) livers transmit the wave faster. It is excellent for diagnosing advanced fibrosis/cirrhosis and monitoring progression. Values >12-15 kPa are highly suggestive of cirrhosis.

C. Cross-Sectional Imaging (CT/MRI)

• Not for routine cirrhosis diagnosis, but crucial for:
  1. Characterizing focal lesions found on USG.
  2. Detailed assessment of vascular anatomy (for transplant or TACE planning).
  3. Evaluating for HCC. Triphasic (multiphase) CT or MRI is the gold standard imaging for HCC diagnosis. The classic hallmark is "wash-in and washout" – the lesion enhances brightly in the arterial phase (hepatic artery supply) and becomes hypodense/intense relative to the liver in the portal venous/delayed phase ^[8][9].
  4. MRI is superior for characterizing certain nodules, assessing iron overload (hemochromatosis), or copper deposition (Wilson's).

3. Invasive Diagnostic Procedures

A. Liver Biopsy – The Histological Gold Standard

• Indications: When diagnosis is uncertain despite non-invasive tests, in suspected autoimmune hepatitis, or to assess disease activity and stage (e.g., NASH activity score).
• Histological Diagnosis: Confirms the triad of bridging fibrosis, regenerative nodules, and architectural distortion ^[5][6].
• Limitations: Invasive, risk of bleeding (correct coagulopathy first), sampling error.

B. Hepatic Venous Pressure Gradient (HVPG) Measurement

• A catheter is placed in the hepatic vein to measure the gradient between the wedged (occluded) and free pressures. This directly measures sinusoidal pressure.
• Normal HVPG: 1-5 mmHg.
• Clinically Significant Portal Hypertension: HVPG ≥10 mmHg – threshold for developing varices and ascites ^[7].
• Used for: Confirming portal hypertension, assessing response to therapy (e.g., beta-blockers for varices), and in clinical trials.

C. Diagnostic Paracentesis

• The first step in the evaluation of new-onset ascites in a cirrhotic patient ^[6].
• Analyze: Cell count (neutrophil count >250/mm³ diagnoses Spontaneous Bacterial Peritonitis), culture, albumin (to calculate SAAG), and cytology if malignancy is suspected.
• Serum-Ascites Albumin Gradient (SAAG): SAAG ≥1.1 g/dL confirms portal hypertension as the cause of ascites (high accuracy).

Active Recall - Diagnosis of Cirrhosis

1. Calculate the Child-Pugh score for a patient with: Albumin 28 g/L, Bilirubin 50 μmol/L, INR 2.0, moderate ascites, and grade 2 encephalopathy. What is their Child-Pugh class and what is the approximate 1-year survival?

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Albumin 28 g/L = 2 pts, Bilirubin 50 μmol/L = 3 pts, INR 2.0 = 2 pts, Moderate Ascites = 3 pts, Grade 2 Encephalopathy = 2 pts. Total = 12 points. This is Child-Pugh Class C. Approximate 1-year survival is 45%.

2. A cirrhotic patient on surveillance ultrasound is found to have a new 2.5 cm solid liver nodule. What is the next definitive diagnostic step, and what imaging finding would confirm hepatocellular carcinoma without needing a biopsy?

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The next step is a multiphasic contrast-enhanced CT or MRI of the liver. The finding that confirms HCC is 'arterial phase hyperenhancement' followed by 'washout' in the portal venous or delayed phases.

3. Explain the pathophysiological reasons for two common hematological findings in cirrhosis: thrombocytopenia and a prolonged prothrombin time (PT).

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Thrombocytopenia: 1) Sequestration of platelets in an enlarged spleen due to portal hypertension (hypersplenism). 2) Reduced hepatic production of thrombopoietin. Prolonged PT: Reduced synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) by the failing liver. Factor VII has the shortest half-life, so PT prolongs early.

4. What is the significance of a Serum-Ascites Albumin Gradient (SAAG) ≥1.1 g/dL in a patient with ascites? What are the two most common causes in this category?

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A SAAG ≥1.1 g/dL indicates that portal hypertension is the cause of the ascites. The two most common causes are Liver Cirrhosis and Heart Failure (congestive hepatopathy).

5. A middle-aged woman presents with pruritus and fatigue. LFT shows isolated elevation of ALP (3x ULN) and GGT. Ultrasound shows no biliary dilation. What is the most specific diagnostic blood test you should order, and what is the likely diagnosis?

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The most specific test is Anti-Mitochondrial Antibody (AMA). The likely diagnosis is Primary Biliary Cholangitis (PBC).

References

^[1] Senior notes: felixlai.md (Causes of liver cirrhosis, HBV most common in HK) ^[2] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (HCC Aetiology) ^[3] Senior notes: felixlai.md (Biochemical tests - CBC, clotting, mechanisms) ^[4] Senior notes: felixlai.md (LFT patterns in cirrhosis) ^[5] Senior notes: felixlai.md (Radiological tests - USG, CT, MRI findings) ^[6] Senior notes: felixlai.md (Diagnostic paracentesis as first step) ^[7] Senior notes: felixlai.md (Pathophysiology of portal hypertension, HVPG thresholds) ^[8] Senior notes: felixlai.md (HCC diagnostic guidelines and radiological features) ^[9] Senior notes: maxim.md (Triphasic CT as gold standard for HCC, AFP) ^[10] Senior notes: felixlai.md (PBC diagnostic criteria) ^[11] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (AFP >400 ng/ml diagnostic of HCC)

Management Algorithm and Treatment Modalities for Liver Cirrhosis

The management of cirrhosis is a lifelong commitment, shifting from a focus on slowing progression and preventing complications in the compensated stage to aggressively managing life-threatening complications and evaluating for transplant in the decompensated stage. The overarching principle is to treat the underlying etiology whenever possible and to use a multidisciplinary approach involving hepatologists, surgeons, radiologists, and transplant teams.

The management strategy can be visualized in the following algorithm, which guides decisions based on the stage of the disease and the presence of specific complications.

1. General Management & Treatment of the Underlying Cause

This is the most critical step, as it can halt progression and even lead to regression of fibrosis in some cases.

• Chronic Hepatitis B (HBV):

  • Goal: Suppress viral replication to undetectable levels (HBV DNA).
  • First-line Agents: Entecavir or Tenofovir (TAF/TDF). These are potent nucleos(t)ide analogs with high barriers to resistance. They are indicated in all cirrhotic patients with detectable HBV DNA, regardless of ALT level ^[1][9].
  • Mechanism: They inhibit the HBV reverse transcriptase, stopping viral DNA synthesis.
  • Monitoring: HBV DNA, LFTs, renal function (for Tenofovir).

• Chronic Hepatitis C (HCV):

  • Goal: Achieve sustained virologic response (SVR), which is a "cure."
  • Agents: Direct-acting antivirals (DAAs) – e.g., Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir. These are oral, well-tolerated, and have >95% cure rates in 8-12 weeks.
  • Mechanism: They target specific non-structural proteins of HCV (NS3/4A protease, NS5A, NS5B polymerase) crucial for viral replication.

• Alcohol-Related Liver Disease (ALD):

  • Cornerstone: Complete, lifelong abstinence. This is non-negotiable and can dramatically improve prognosis.
  • Support: Referral to addiction services, counseling, and potentially medications like acamprosate or naltrexone (if liver function allows).
  • Nutrition: Correct malnutrition and specific vitamin deficiencies (especially B vitamins).

• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/MASH):

  • Goal: Weight loss and control of metabolic drivers.
  • Lifestyle: Weight loss of 7-10% is the most effective therapy. Achieved through calorie restriction and exercise (150+ min/week).
  • Pharmacotherapy: For patients with MASH and significant fibrosis, consider GLP-1 agonists (e.g., semaglutide) or other metabolic agents. Vitamin E may be considered in non-diabetic patients.

• Autoimmune Hepatitis (AIH):

  • Goal: Induce and maintain remission to prevent progression.
  • First-line: Prednisolone (induction) followed by Azathioprine (maintenance). Budesonide (a topical steroid with high first-pass metabolism) may be used in non-cirrhotic patients.
  • Mechanism: Suppress the immune-mediated attack on hepatocytes.

• Primary Biliary Cholangitis (PBC):

  • First-line: Ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day. It improves liver biochemistry, delays histological progression, and improves transplant-free survival ^[10][11].
  • Mechanism: Thought to replace toxic endogenous bile acids, stimulate bile flow, and have anti-apoptotic effects on cholangiocytes.
  • Second-line: Obeticholic acid (a FXR agonist) for patients with an inadequate biochemical response to UDCA.

• Genetic/Metabolic Disorders:

  • Hemochromatosis: Weekly therapeutic phlebotomy to deplete iron stores. Target ferritin < 100 ng/mL.
  • Wilson's Disease: Copper chelation with D-penicillamine or Trientine. Zinc acetate (induces metallothionein, blocking copper absorption) for maintenance.
  • Alpha-1 Antitrypsin Deficiency: Supportive. No specific therapy for the liver disease other than avoiding alcohol/smoking. Augmentation therapy is for lung disease.

2. Management of Complications

A. Ascites and Edema

• Step 1: Diagnostic Paracentesis – Always perform first to rule out SBP ^[6].
• Step 2: Dietary Sodium Restriction – Strict < 2g/day (88 mmol/day). This is often the hardest part for patients.
• Step 3: Diuretic Therapy:
  • Start with: Spironolactone (an aldosterone antagonist). Why? Cirrhosis causes secondary hyperaldosteronism. Start at 100mg/day.
  • Add-on: Furosemide 40mg/day if response is inadequate. The 100:40 ratio helps maintain normokalemia.
  • Goal: Weight loss of 0.5-1.0 kg/day in patients with edema, 0.3-0.5 kg/day without edema. Monitor renal function and electrolytes.
• Refractory Ascites: Defined as failure to respond to sodium restriction and high-dose diuretics (spironolactone 400mg/day + furosemide 160mg/day) or rapid recurrence after therapeutic paracentesis.
  • Therapeutic Paracentesis: For large-volume (>5L) taps, administer IV albumin (8g per liter removed) to prevent post-paracentesis circulatory dysfunction (PPCD) ^[6].
  • Transjugular Intrahepatic Portosystemic Shunt (TIPS): A radiologically placed stent connecting the portal vein to a hepatic vein, dramatically reducing portal pressure.
    • Indication: Refractory ascites or recurrent ascites requiring frequent paracentesis.
    • Contraindications: Severe hepatic failure (Child-Pugh >11, MELD >18), severe hepatic encephalopathy, cardiac/pulmonary failure, portal vein thrombosis.

B. Spontaneous Bacterial Peritonitis (SBP)

• Diagnosis: Ascitic fluid neutrophil count > 250 cells/mm³.
• Empirical Antibiotics: IV 3rd generation cephalosporin (e.g., Cefotaxime) for 5-7 days. Adjust based on culture.
• Albumin Infusion: Give IV albumin (1.5 g/kg on day 1, 1.0 g/kg on day 3) to reduce the risk of hepatorenal syndrome and improve survival.
• Secondary Prophylaxis: After one episode of SBP, lifelong Norfloxacin 400mg daily or Ciprofloxacin is indicated to prevent recurrence.

C. Acute Variceal Hemorrhage

A life-threatening emergency requiring coordinated, urgent management.

• Resuscitation & General Measures:
  • Secure airway if encephalopathic.
  • Restrictive transfusion strategy – target Hb ~7-8 g/dL. Over-transfusion increases portal pressure and re-bleeding risk ^[2].
  • Correct coagulopathy (FFP, Vitamin K) and thrombocytopenia (platelets if < 50,000).
• Pharmacological Therapy (START IMMEDIATELY):
  • Vasoactive Drugs: Terlipressin (preferred – reduces portal inflow by splanchnic vasoconstriction) or Octreotide/Somatostatin analogs. Continue for 2-5 days.
  • IV Antibiotics: Ceftriaxone for 7 days. Infection is a major precipitant of re-bleeding and mortality.
• Endoscopic Therapy (Within 12 hours):
  • Gold Standard: Endoscopic Variceal Band Ligation (EVL). Bands are placed on the varices, causing them to thrombose and slough off.
  • Alternative: Sclerotherapy (if banding technically difficult).
• Rescue Therapy for Uncontrolled Bleeding:
  • Balloon Tamponade (Sengstaken-Blakemore tube) – temporary bridge.
  • TIPS – very effective at controlling hemorrhage as a salvage procedure.
• Secondary Prophylaxis: Start non-selective beta-blockers (NSBB) – Propranolol or Carvedilol – to reduce portal pressure. Mechanism: β1-blockade reduces cardiac output; β2-blockade allows unopposed α-adrenergic tone, causing splanchnic vasoconstriction. Titrate to heart rate ~55-60 bpm. If NSBB contraindicated, perform serial EVL.

D. Hepatic Encephalopathy (HE)

• Identify & Treat Precipitants: Infection (especially SBP), GI bleed, constipation, dehydration, medications.
• First-Line Therapy:
  • Lactulose: A non-absorbable disaccharide. Gut bacteria ferment it to organic acids, lowering colonic pH. This "traps" ammonia (NH3) as ammonium (NH4+), which is not absorbed, and acts as an osmotic laxative to clear ammonia-producing bacteria. Titrate to 2-4 soft stools per day ^[4].
  • Rifaximin: A non-absorbable antibiotic that modulates gut flora, reducing ammonia production. Used as an add-on to lactulose for recurrent episodes.
• Nutrition: No long-term protein restriction. Provide adequate calories to prevent catabolism.

E. Hepatorenal Syndrome (HRS)

• Definition: Functional renal failure in advanced cirrhosis, a diagnosis of exclusion.
• Treatment:
  • IV Albumin (1g/kg on day 1, then 20-40g/day) for volume expansion.
  • Vasoconstrictors: Terlipressin (or norepinephrine in ICU) to counteract splanchnic vasodilation. This increases effective arterial blood volume and renal perfusion.
  • TIPS can be effective in selected patients.
  • Ultimate Therapy: Liver transplantation.

3. Management of Hepatocellular Carcinoma (HCC) in Cirrhosis

The choice of therapy depends on tumor stage, liver function (Child-Pugh), and patient performance status. The Hong Kong Liver Cancer (HKLC) Staging System is commonly used locally ^[7][8].

A. Curative Therapies (for Early-Stage HCC):

• Hepatic Resection:
  • Ideal Candidate: Single tumor, Child-Pugh Class A cirrhosis, no clinically significant portal hypertension, and adequate future liver remnant (FLR >40%). Portal hypertension is assessed by the presence of varices, splenomegaly with thrombocytopenia, or HVPG ≥10 mmHg ^[8][12].
  • Advantage: Potential cure with preservation of native liver.
  • Disadvantage: High recurrence rate (~70% at 5 years) due to "field change" in the cirrhotic liver.
• Liver Transplantation:
  • Ideal Candidate: Meets Milan Criteria (single ≤5cm, or ≤3 nodules each ≤3cm, no vascular invasion/extrahepatic spread) and has decompensated cirrhosis (Child-Pugh B/C).
  • Advantage: Cures both the cancer and the underlying liver disease.
  • Contraindications: Macroscopic vascular invasion, extrahepatic metastasis, active infection, active substance abuse.
  • Bridging Therapy: While on the waitlist, treatments like TACE or RFA are used to prevent tumor progression.
• Local Ablation (e.g., Radiofrequency Ablation - RFA):
  • Ideal Candidate: Small tumors (< 3 cm), ≤3 nodules, not suitable for resection/transplant. Often used for lesions deep in the liver parenchyma.
  • Mechanism: Image-guided insertion of a needle electrode that generates heat, destroying the tumor.

B. Palliative/Locoregional Therapies (for Intermediate-Stage HCC):

• Transarterial Chemoembolization (TACE):
  • Ideal Candidate: Large or multifocal HCC, Child-Pugh A/B, no main portal vein thrombosis, no extrahepatic spread.
  • Mechanism: Catheter is advanced into the hepatic artery branches feeding the tumor. A mixture of chemotherapeutic drug (e.g., doxorubicin) and an embolic agent (e.g., lipiodol/gelfoam) is injected. This achieves high local drug concentration and cuts off the tumor's blood supply (HCC is hypervascular and fed predominantly by the hepatic artery).
  • Contraindications: Decompensated cirrhosis (Child-Pugh C), main portal vein thrombosis (risk of liver infarction), extensive tumor burden (>50% liver involvement), poor performance status ^[7][13].
• Transarterial Radioembolization (TARE / SIRT): Uses radioactive microspheres (Yttrium-90). Particularly useful for tumors with portal vein thrombosis.

C. Systemic Therapy (for Advanced-Stage HCC):

• First-line: Atezolizumab (anti-PD-L1) + Bevacizumab (anti-VEGF). Immunotherapy + anti-angiogenic combination.
• Other options: Lenvatinib (multi-kinase inhibitor), Sorafenib (the original standard, now often second-line).

4. Liver Transplantation

This is the definitive treatment for eligible patients with decompensated cirrhosis or early HCC within criteria.

• Indications: End-stage liver disease (Child-Pugh C, MELD score ≥15), HCC within Milan/UCSF criteria, acute liver failure, certain metabolic diseases.
• Contraindications (Absolute): Active/uncontrolled infection/sepsis outside biliary tree, extrahepatic malignancy, advanced cardiopulmonary disease, active substance abuse, inability to comply with lifelong immunosuppression.
• Prioritization: In HK, the MELD score is used. For HCC patients meeting Milan criteria, they receive a standard "exception score" to reflect their mortality risk from cancer while waiting.
• Post-Transplant Management: Lifelong immunosuppression (e.g., tacrolimus, mycophenolate) to prevent rejection, with monitoring for side effects (renal impairment, diabetes, hypertension, infection, malignancy).

Active Recall - Management of Cirrhosis

1. A patient with decompensated cirrhosis due to Hepatitis B presents with massive ascites refractory to maximum diuretic doses (spironolactone 400mg + furosemide 160mg daily) and requires weekly large-volume paracentesis. What is the next most appropriate interventional treatment to consider, and what is one major contraindication to its use?

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Transjugular Intrahepatic Portosystemic Shunt (TIPS). A major contraindication is severe hepatic failure (e.g., Child-Pugh score >11, MELD >18) or severe, refractory hepatic encephalopathy.

2. Outline the immediate (first 12 hours) management steps for a cirrhotic patient presenting with hematemesis and shock, suspected to be from variceal bleeding.

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1. Resuscitate: Secure airway if needed, two large-bore IVs, restrictive blood transfusion (target Hb ~7-8 g/dL), correct coagulopathy. 2. Start IV vasoactive drug (Terlipressin or Octreotide). 3. Start IV antibiotics (Ceftriaxone). 4. Arrange for urgent upper endoscopy with band ligation (within 12 hours).

3. What is the first-line pharmacological therapy for Primary Biliary Cholangitis (PBC), what is the standard dose, and what is its mechanism of action?

Your answer

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Ursodeoxycholic acid (UDCA). Dose: 13-15 mg/kg/day. Mechanism: It replaces toxic hydrophobic bile acids, stimulates hepatobiliary secretion, and has anti-apoptotic and anti-inflammatory effects on cholangiocytes.

4. According to the Milan Criteria, which a patient must meet to be eligible for liver transplantation for HCC, what are the specifications for tumor size and number?

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Single lesion ≤5 cm in diameter, OR up to 3 lesions each ≤3 cm in diameter. There must be no evidence of gross vascular invasion or extrahepatic metastasis.

5. Explain why non-selective beta-blockers (e.g., propranolol) are used for primary and secondary prophylaxis of variceal bleeding in cirrhosis, including the pharmacological rationale.

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They reduce portal pressure through a dual mechanism: 1) Beta-1 blockade reduces cardiac output, decreasing portal inflow. 2) Beta-2 blockade allows unopposed alpha-adrenergic activity, causing splanchnic vasoconstriction, which further reduces portal venous inflow.

References

^[1] Senior notes: felixlai.md (Treatment of hepatitis B with nucleoside analogues) ^[2] Senior notes: felixlai.md (Initial management of variceal hemorrhage - fluid restriction, blood transfusion thresholds) ^[3] Senior notes: felixlai.md (Management of ascites - diuretics, paracentesis, TIPS) ^[4] Senior notes: felixlai.md (Medical treatment of hepatic encephalopathy - lactulose, rifaximin) ^[5] Senior notes: felixlai.md (Management of hepatorenal syndrome - terlipressin + albumin) ^[6] Senior notes: felixlai.md (Diagnostic paracentesis as first step, albumin replacement for large-volume taps) ^[7] Senior notes: felixlai.md (Hong Kong Liver Cancer Staging System, TACE indications/contraindications) ^[8] Senior notes: maxim.md (Liver resection prerequisites, Milan/UCSF criteria for transplant) ^[9] Senior notes: felixlai.md (Etiology of cirrhosis - HBV most common) ^[10] Senior notes: felixlai.md (PBC treatment - UDCA) ^[11] Senior notes: felixlai.md (PBC - UDCA improves survival) ^[12] Senior notes: maxim.md (Resectability factors for HCC) ^[13] Senior notes: felixlai.md (Contraindications to TACE)

Common Complications of Liver Cirrhosis

The transition from compensated to decompensated cirrhosis is marked by the development of specific, often life-threatening complications. These arise from the two fundamental consequences of cirrhosis: portal hypertension and hepatocellular failure. Understanding each complication's unique pathophysiology is key to anticipating, diagnosing, and managing them.

1. Ascites and Edema

The most common complication of cirrhosis and the most frequent first decompensating event. ^[1]

• Pathophysiology: This isn't just about low albumin. It's a hemodynamic cascade:
  1. Portal Hypertension (HVPG ≥10 mmHg) ^[2] → Splanchnic arterial vasodilation (from excess nitric oxide).
  2. This leads to effective arterial hypovolemia (the arteries are too dilated, so the body senses low blood volume).
  3. This triggers the activation of the Renin-Angiotensin-Aldosterone System (RAAS) and the sympathetic nervous system.
  4. Result: Sodium and water retention by the kidneys.
  5. The retained fluid, driven by the high portal pressure and hypoalbuminemia (which reduces plasma oncotic pressure), leaks into the peritoneal cavity as ascites and into the interstitial spaces as peripheral edema.
• Clinical Features: Abdominal distension, increased waist size, flank dullness, shifting dullness, fluid thrill. Lower limb pitting edema is often concomitant.
• Key Point: Diagnostic paracentesis is the FIRST step in the evaluation of new-onset ascites to rule out infection (SBP) and confirm the cause ^[1].

2. Spontaneous Bacterial Peritonitis (SBP)

A life-threatening infection of ascitic fluid without a surgically treatable source. It's a classic example of how cirrhosis disrupts host defense.

• Pathophysiology:
  • Bacterial Translocation: Gut bacteria migrate across the edematous, congested intestinal wall into the mesenteric lymph nodes.
  • Impaired Clearance: Portosystemic shunting bypasses the liver's Kupffer cells (the body's filter), allowing bacteria to reach the systemic circulation.
  • Vulnerable Fluid: Ascitic fluid has low opsonic activity (low complement and immunoglobulin levels), making it a poor culture medium for killing bacteria ^[3].
• Diagnosis: Ascitic fluid neutrophil count > 250 cells/mm³. Culture may be negative (Culture-Negative Neutrocytic Ascites), but treatment is still required.
• Clinical Features: May be subtle – fever, mild abdominal pain, worsening encephalopathy, or renal function. Can also present with no symptoms.

3. Variceal Hemorrhage

The most dramatic and immediately life-threatening complication. Mortality from the first bleed is 20-30%.

• Pathophysiology: Portal hypertension (HVPG ≥12 mmHg) ^[2] forces blood through collateral vessels. The esophageal and gastric varices are thin-walled and prone to rupture. Rupture risk is driven by the tension on the variceal wall (Laplace's law: tension ∝ pressure x radius / wall thickness).
• Clinical Features: Sudden, painless, large-volume hematemesis (vomiting bright red blood) and/or melena. May present with hypovolemic shock.
• Why it's deadly: The combination of hypovolemia, impaired synthetic function (coagulopathy), and the stress of bleeding can precipitate hepatic encephalopathy, hepatorenal syndrome, and infection.

4. Hepatic Encephalopathy (HE)

A spectrum of neuropsychiatric disturbances caused by the liver's failure to detoxify gut-derived substances.

• Pathophysiology: The central theory involves hyperammonemia. The failing liver cannot convert ammonia (NH₃) to urea. Portosystemic shunting also allows ammonia to bypass the liver. Ammonia crosses the blood-brain barrier, causing astrocyte swelling and cerebral edema, disrupting neurotransmission.
• Clinical Spectrum: Ranges from minimal HE (poor concentration, psychometric defects) to overt HE (confusion, personality change, asterixis - "liver flap", drowsiness, coma).
• Precipitants: Always search for a trigger: Infection (SBP!), GI bleed, constipation, dehydration, electrolyte imbalance, sedatives, or high protein intake ^[4].

5. Hepatorenal Syndrome (HRS)

A functional, potentially reversible renal failure in advanced cirrhosis. It is a diagnosis of exclusion.

• Pathophysiology: A severe progression of the same hemodynamic derangement causing ascites.
  1. Profound splanchnic vasodilation leads to severe effective hypovolemia.
  2. This causes intense renal vasoconstriction (via RAAS and SNS) to maintain systemic blood pressure.
  3. The result is drastically reduced renal perfusion and glomerular filtration rate (GFR), but the renal tubules themselves are intact (hence "functional").
• Types:
  • Type 1 HRS: Rapid, progressive renal failure (doubling of creatinine to >2.5 mg/dL in < 2 weeks). Often triggered by SBP or GI bleed. Dismal prognosis.
  • Type 2 HRS: Steady, moderate renal impairment (creatinine 1.5-2.5 mg/dL). Usually associated with refractory ascites.
• Diagnostic Clues: Oliguria, rising creatinine, very low urine sodium (< 10 mmol/L), and bland urine sediment (no cells/casts).

6. Hepatocellular Carcinoma (HCC)

The most common primary liver cancer and a major cause of death in cirrhotic patients. Cirrhosis is the single greatest risk factor.

• Epidemiology in HK: 80% of HCC in Hong Kong occurs in HBsAg-positive individuals ^[5]. HCC complicates HCV almost exclusively on a background of cirrhosis (100%), while it can occur in non-cirrhotic livers in HBV (20%) due to HBV's direct oncogenic effect ^[6].
• Pathogenesis: Chronic inflammation, hepatocyte regeneration, and genetic mutations (e.g., p53 from aflatoxin) lead to dysplastic nodules and eventually HCC. The whole cirrhotic liver is at risk ("field cancerization").
• Why Prognosis is Often Poor: Patients are often asymptomatic until the tumor is large (>8 cm) ^[7]. The underlying cirrhosis limits treatment options (resection, transplant) and predisposes to liver failure post-treatment. HCC also has a high propensity for vascular invasion (portal vein thrombosis) and intrahepatic metastasis ^[5].
• Screening: All cirrhotic patients should have 6-monthly ultrasound and AFP surveillance.

7. Other Cardiopulmonary Complications

• Hepatic Hydrothorax: Pleural effusion (usually right-sided) due to passage of ascitic fluid through diaphragmatic defects. Managed like ascites.
• Hepatopulmonary Syndrome (HPS): Triad of cirrhosis, hypoxemia, and intrapulmonary vascular dilatations. Patients develop platypnea (shortness of breath when upright) and orthodeoxia (worsening hypoxia when upright). Clubbing is common.
• Portopulmonary Hypertension (POPH): Pulmonary arterial hypertension (mean PA pressure >25 mmHg) in the setting of portal hypertension. Presents with dyspnea, fatigue, and can lead to right heart failure.
• Cirrhotic Cardiomyopathy: Impaired cardiac contractility and response to stress in the setting of cirrhosis, despite a normal or high resting cardiac output. Can unmask during procedures like TIPS or transplant.

8. Complications Specific to Cholestatic Liver Diseases (PBC/PSC)

• Pruritus: Debilitating itching due to retained bile acids and other pruritogens. Worse at night.
• Steatorrhea & Fat-Soluble Vitamin (A, D, E, K) Deficiency: Due to reduced bile acid secretion, impairing fat digestion and absorption. Can lead to night blindness (Vit A), osteomalacia/osteoporosis (Vit D), neuropathy (Vit E), and coagulopathy (Vit K).
• Hepatic Osteodystrophy: Metabolic bone disease (osteoporosis/osteopenia) from vitamin D deficiency, chronic inflammation, and direct inhibitory effects of cholestasis on osteoblasts.
• Hyperlipidemia: Particularly in PBC, with a characteristic elevation of lipoprotein-X. Notably, this does not seem to increase atherosclerotic risk.
• Cholangiocarcinoma: A major life-threatening complication of Primary Sclerosing Cholangitis (PSC). The risk is lifelong, and screening with MRI/MRCP and CA19-9 is recommended.

Active Recall - Complications of Cirrhosis

1. What is the most common first decompensating event in a patient with previously compensated liver cirrhosis, and what is the fundamental hemodynamic derangement that leads to it?

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The most common first decompensating event is ascites. The fundamental derangement is portal hypertension leading to splanchnic arterial vasodilation, effective arterial hypovolemia, activation of RAAS, and renal sodium and water retention.

2. A cirrhotic patient with known ascites presents with mild confusion and a low-grade fever but no abdominal pain. What is the most critical complication you must rule out immediately, and what is the diagnostic test?

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Spontaneous Bacterial Peritonitis (SBP). The diagnostic test is a diagnostic paracentesis, looking for an ascitic fluid neutrophil count >250 cells/mm³.

3. Explain why a patient with alcoholic cirrhosis is at high risk for both Hepatorenal Syndrome (HRS) and Hepatic Encephalopathy (HE) following an episode of variceal bleeding.

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Variceal bleeding causes hypovolemia, which worsens the effective arterial hypovolemia of cirrhosis, triggering intense renal vasoconstriction and precipitating HRS. The blood in the GI tract is broken down by bacteria into ammonia and other neurotoxins. The cirrhotic liver cannot detoxify this increased ammonia load, and portosystemic shunting allows it to reach the brain, precipitating HE.

4. In the context of Hong Kong, why is screening for Hepatocellular Carcinoma (HCC) particularly important in patients with cirrhosis, and what is the recommended surveillance method?

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Because Hepatitis B (HBV) is the leading cause of cirrhosis in Hong Kong, and HBV carriers have a high lifetime risk of developing HCC. The recommended surveillance is abdominal ultrasound and serum Alpha-fetoprotein (AFP) measurement every 6 months.

5. What are the two key pathophysiological reasons for the development of spontaneous bacterial peritonitis (SBP) in a cirrhotic patient with ascites?

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1) Bacterial translocation from the gut due to intestinal wall edema and altered microbiota. 2) Impaired immune defense in the ascitic fluid due to low opsonic activity and portosystemic shunting that bypasses the liver's Kupffer cells.

References

^[1] Senior notes: felixlai.md (Ascites as most common complication, diagnostic paracentesis as first step) ^[2] Senior notes: felixlai.md (HVPG thresholds for ascites and variceal bleeding) ^[3] Senior notes: felixlai.md (Low ascitic fluid protein in SBP) ^[4] Senior notes: felixlai.md (Precipitants of hepatic encephalopathy) ^[5] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (HCC aetiology in HK, vascular invasion) ^[6] Senior notes: felixlai.md (HBV vs HCV and HCC on cirrhotic/non-cirrhotic liver) ^[7] Senior notes: felixlai.md (HCC presents late, symptoms at >8cm)