creation date: 2025-11-24 17:45
tags: Pathologies
Cirrhosis
Background
Definitions
Cirrhosis is characterized by fibrosis and nodule formation of the liver secondary to chronic injury. This condition is associated with permanent loss of function and is irreversible.
Etiology
Chronic liver diseases progress to cirrhosis. In the developed world, the most common causes are:
- Hepatitis C virus
- Alcoholic liver disease
- Metabolic dysfunction associated steatohepatitis (MASH)
In the developing world, the most common causes are:
- Hepatitis B virus
- Hepatitis C virus
Other causes include:
- Autoimmune hepatitis
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- Hemochromatosis
- Wilson disease
- Alpha-1 antitrypsin deficiency
- Budd-Chiari syndrome
- Drug-induced liver cirrhosis
- Chronic right-sided heart failure
If the etiology is unclear, the condition is referred to as cryptogenic cirrhosis.
Pathogenesis and Pathophysiology
Development of fibrosis
The cells of the liver, hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells play roles in the development of cirrhosis.
Hepatic stellate cells normally store vitamin A. When exposed to cytokines, they activate and transform into myofibroblasts, depositing collagen and causing fibrosis.
Sinusoidal endothelial cells are part of the endothelial lining which are fenestrated to allow for exchange of fluids and nutrients between the sinusoids and the hepatocytes. Chronic alcohol use result in their defenestration and causes perisinusoidal fibrosis.
Finally, Kupffer cells release mediators when exposed to insults which are harmful to hepatocytes. Damaged hepatocytes also release reactive oxygen species and inflammatory mediators which further worsen the pathogenesis of fibrosis.
Development of portal hypertension and it’s sequelae
The major cause of morbidity and mortality is cirrhotic patients is portal hypertension and hyperdynamic circulation.
This occurs due to fibrosis and changes to vasoregulation. Intrahepatically, the loss of sinusoidal endothelial cells reduce NO production which increase intrahepatic vasoconstriction and resistance, subsequently increasing pressure. Collateral circulation (eg. esophageal varices, gastric varicies, caput medusae) is formed to compensate for the intrahepatic hypertension which can rupture and result in significant bleed.
Systemically, an increase in NO production occurs to compensate for portal hypertension which results in decreased systemic resistance which activates the RAAS system leading to sodium and water retention. Persistent RAAS activation result in pronounced renal vasoconstriction and drop in GFR resulting in hepatorenal syndrome. Additionally, RAAS activation and ADH release can result in hyponatremia. Excessive accumulation of NO in the lung vessels cause pulmonary vasodilation as seen with hepatopulmonary syndrome.
Elevated portal pressure causes congestion distal to the liver. Congestion of the splenic vein results in the accumulation of blood in the spleen (ie. splenomegaly) and splenic sequestration (typically, thrombocytopenia → leukocytopenia → anemia).
Increased pressure to the mesenteric veins (hydrostatic pressure) pushes fluid into the peritoneum (ie. ascites). This is exacerbated by hypoalbuminemia but portal hypertension is required for the development of ascites. Patients with ascites are at risk of lymphatic spread of bacteria to the ascitic fluid causing spontaneous bacterial peritonitis.
Development of liver insufficiency and it’s manifestations
With the loss of fenestration and fibrosis, the substrate exchange of the liver is impaired. Normal liver function, listed below, is thus lost/impaired:
- Energy metabolism
- Synthesis (eg. gluconeogenesis)
- Regulation (of blood glucose)
- Storage (of glycogen, lipoproteins, fat-soluble vitamins (A, K, E, D), folate, vitamin B12, iron, copper)
- Detoxification and clearance/excreation (urea, cytochrome-P450, ethanol)
- Erythropoiesis in fetus (week 6 gestation to birth)
A failure to clear ammonia leads to cerebral edema and hepatic encephalopathy.
Clinical Presentation
Signs & Symptoms
Compensated cirrhosis may be asymptomatic or nonspecific symptoms.
Nonspecific symptoms include:
- Anorexia
- Weight loss
- Weakness
- Fatigue
- Pruritus
- Muscle cramps
- Sexual dysfunction
Decompensated cirrhosis may present differently depending on the complication.
Symptoms of hepatic decompensation include:
- Jaundice
- Signs of upper gastrointestinal bleeding
- Abdominal distension from ascites
- Confusion or altered execute function (hepatic encephalopathy)
Physical examination may find:
- Jaundice
- Spider angiomata
- Gynecomastia
- Ascites
- Splenomegaly
- Palmar erythema
- Asterixis
In females, chronic anovulation is common which manifests as:
- Amenorrhea
- Irregular menstrual bleeding
In males, hypogonadism may develop, which manifests as:
- Impotence
- Infertility
- Loss of sexual drive
- Testicular atrophy
History & Physical Exam
History should elicit the extent of symptom burden. A thorough past medical history may find conditions relating to the underlying causes of cirrhosis.
A thorough physical exam for the signs and symptoms of cirrhosis. In particular:
- Decreasing blood pressure
- Skin findings (jaundice)
- Head and neck for parotid gland enlargement and fetor hepaticus
- Chest findings for gynecomastia
- Abdominal findings for ascites, hepatomegaly, splenomegaly, caput medusae
- Cruveilhier-Baumgarten murmur (venous murmur heard ) may be heard
Risk factors
Diagnosis
Criteria
In patients suspected of cirrhosis, abdominal ultrasound is the first evaluation of the liver parenchyma and detection of extrahepatic manifestations.
A liver biopsy is required for definitive diagnosis but is generally not necessary if clinical, laboratory, and radiologic data supports the diagnosis as management would not change with definitive diagnosis.
Work-up
Laboratory tests
- Liver enzymes (may initially elevate but as cirrhosis progresses, hepatocytes no longer produce)
- Serum bilirubin
- Serum albumin and PT/INR
- Glucose
- Electrolytes/creatinine (for hyponatremia/renal function)
- CBC (for thrombocytopenia and anemia)
For patients suspected of decompensated cirrhosis:
- Paracentesis and serum-to-ascites albumin gradient (SAAG) - high SAAG (≥11 g/L) is indicative of portal hypertensive ascites
- Esophagogastroduodenoscopy (EGD) for varices
- Ammonia levels if HE suspected
Imaging
Ultrasound, CT, and MRI are typically the modalities used. Findings include:
- Shrunken, irregular, nodular liver
- Caudate lobe hypertrophy may be seen
Imaging may also find varices and ascites in patients with portal hypertension. At early stages, imaging is approximately 80% sensitive and 80% specific for cirrhosis.
Prognosis
Scoring systems can be used to determine the severity of disease.
- MELD-Na (3 month mortality predictor for liver transplant priority)
- Child-Pugh score
Differential
Various conditions may present with ascites:
- High SAAG (≥ 11 g/L):
- Right heart failure
- Portal vein thrombosis
- Budd-Chiari syndrome
- Hepatocellular carcinoma
- Low SAAG (< 11 g/L)
- Pancreatitis
- Tuberculosis (causing peritoneal inflammation)
- Peritoneal malignancy
- Nephrotic syndrome (low serum albumin)
Red Flags / Complications
Major complications of cirrhosis includes:
- Variceal hemorrhage (10% mortality for esophageal varice rupture)
- Ascities
- Spontaneous bacterial peritonitis (20-30% mortality in hospital)
- Hepatic encephalopathy
- Hepatocellular carcinoma
- Hepatorenal syndrome
- Hepatopulmonary syndrome
Development of these symptoms mean decompensation of cirrhosis. Decompensated cirrhosis may need liver transplantation.
Management
General measures
Slowing or reversing progression of liver disease
While cirrhosis is generally irreversible at later stages, some chronic liver diseases still respond to treatment. Thus, some causes should indicate specific therapies.
- Hepatitis C: antiviral treatment for sustained virologic response
- Alcoholic liver disease: abstinence from alcohol
Preventing superimposed insults to the liver
Prevention of further injuries include:
- Vaccination against hepatitis A and B for those who are not immune already
- Avoidance of hepatotoxins (medications, alcohol, certain herbal remedies)
Adjustment of medication dosing (or discontinuing)
Impaired hepatic metabolism or kidney excretion may result in increased risk of adverse events. This is primarily due to a decrease in first-pass metabolism due to:
- Alterations in hepatic blood flow
- Portosystemic shunting
- Changes to cytochrome P450 activity
Managing symptoms and laboratory abnormalities
Muscle cramps:
- Stretching (forceful contraction of opposing muscle group)
- Vitamin B, vitamin E, or vitamin K2
Umbilical hernia:
- Surgical if ruptured or incarcerated, consider if symptomatic
- Conservative with asymptomatic due to high risk with decompensated cirrhosis and ascites
Hyponatremia:
- Due to hemodynamic changes causing water retention
- Management of hyponatremia
Thrombocytopenia or elevated INR:
- Treatment typically only needed prior to invasive procedure with moderate/high risk of bleeding or during active bleeding
- Method of raising platelet depends on individual factors but include transfusions, thrombopoietin receptor agonist, and treatment of reversible condition such as infection
Treatment of complications
General measures include:
- Judicious diuresis
- Avoidance of PPIs unless necessary (spontaneous bacterial peritonitis)
- Treating and avoiding infections (bacterial peritonitis and secondary infections)
- Avoidance of nephrotoxicity and over-diuresis (hepatorenal syndrome)
The management of a few complications are described as follow:
Esophageal/gastric/rectal varices
Prophylactic:
- Non-cardioselective beta-blockers
- Variceal band ligation
Active bleed: - Fluid resuscitation
- Prophylactic antibiotics
- IV octreotide (splanchnic vasoconstrictor)
- Band ligation prn
Ascites
- Sodium restriction
- Diuretics (spironolactone ± furosemide)
- Large volume paracentesis (>5 L) with albumin
- Transjugular intrahepatic portosystemic shunt (TIPS)
- Transplant
For spontaneous bacterial peritonitis, antibiotics are promptly used (eg. cefotaxime ± fluoroquinolone)
Hepatorenal syndrome
- IV octreotide + midodrine (splanchnic vasoconstrictors)
- Albumin (increase capillary oncotic pressure)
- IV epinephrine
- NO fluid resuscitation
Hepatic encephalopathy
- Lactulose (lowers pH which acidifies ammonia to ammonium which is not reabsorbed and thus excreted)
- Rifaximin (non-absorbable antibiotic)
Increased hepatocellular carcinoma risk
Abdominal ultrasound for screening of HCC is indicated every 6 months.
Liver Transplantation
Liver transplant is the definitive treatment for patients with decompensated cirrhosis. Eligibility may vary but generally depends on:
- Severity of disease
- Quality of life
- Absence of contraindications