Cirrhosis of liver condition characterized by hepatic cell necrosis, resulting in the collapse of hepatic architecture and nodular regeneration along with regenerative attempts leading to the formation of nodules.
It is a progressive condition and develops over many years, slowly. Eventually, unabated, it could end the liver function.
Cirrhosis is caused by many different diseases, the common factor being long-term, continuous damage to the liver needs to occur.
Earlier alcohol was the leading cause but now viral infections are major contributors.
Laennec derived the term cirrhosis [scirrhus in Greek means orange surface {seen on biopsy}]
Cirrhosis is an irreversible process.
However, the symptoms may not develop for years and are often not specific like lack of appetite, fatigue, and weight loss. Manifestations like portal hypertension, ascites, hepatic encephalopathy, liver failure, and kidney failure occur late in the course.
Treatment is supportive. Liver transplant has improved the prognosis.
Many patients die from the disease in their fifth or sixth decade of life.
Cirrhosis is one of the top 15 causes of death worldwide but ranks fourth in Europe and ninth in US.
Causes and Diseases That Could Lead to Cirrhosis
Hepatitis C is the most common cause of cirrhosis in developed countries. In Asia and Africa, hepatitis B tops.
Cryptogenic cirrhosis is the term given to cirrhosis where cause is not known. As more and more specific causes are being identified, the number of cases attributed to it is reducing.
A list of causes of cirrhosis
- Hepatitis C
- Alcoholic liver disease
- Combined hepatitis C and alcoholic liver disease
- Cryptogenic causes
- Many cases actually are due to non-alcoholic fatty liver disease
- Hepatitis B
- Autoimmune hepatitis
- Primary biliary cirrhosis
- Secondary biliary cirrhosis – Associated with chronic extrahepatic bile duct obstruction
- Primary sclerosing cholangitis
- Granulomatous disease- sarcoidosis
- Type IV glycogen storage disease
- Drug-induced
- Methotrexate
- Alpha-methyldopa
- Amiodarone
- Venous outflow obstruction – Eg, Budd-Chiari syndrome, veno-occlusive disease
- Right-sided cardiac failure
- Hemochromatosis
- Excessive iron absorption and deposition in the liver
- Wilson disease
- Excessive deposition of copper l
- Galactosemia
- Deficiency of the enzyme galactose-1-phosphate-uridyl transferase
- Galactose from milk diet is not metabolized
- Alpha-1-antitrypsin deficiency
- Nutrition
- Diet low in methionine and choline may cause fatty liver and cirrhosis.
- A diet rich in unsaturated fats
- Infections
- Malaria
- Kala-azar
- Schistosomiasis
- Toxins
- Aflatoxin-contaminated food
Cryptogenic: The cause of cirrhosis is not identified. Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic fatty liver disease (NAFLD).
Pathophysiology of Cirrhosis
Cirrhosis is a late stage of hepatic fibrosis which has resulted in the destruction of normal hepatic architecture. It may take years for the progression of a liver injury to cirrhosis.
The characteristic feature of cirrhosis regenerative nodules surrounded by dense fibrosis.
Thus there are two elements
- Hepatic fibrosis
- Regenerating liver cells [which attempt regeneration but instead end up in nodule]
The initial event after an injury is fibrosis which is a kind of scarring in the repair process of the injury and is marked an excess deposition of extracellular matrix [collagens, glycoproteins, proteoglycans] in the liver.
Stellate cells[ Ito cell] get activated into collagen-forming cells by a variety of cytokines and hepatic growth factors released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury.
Increased collagen deposition in the space of Disse (the space between hepatocytes and sinusoids). Capillarization and constriction of sinusoids [stellate cells have contractile properties] by stellate cells contribute to the development of portal hypertension.
[Per se, fibrosis causes no symptoms but can lead to portal hypertension as it can affect the blood flow.]
Cirrhosis occurs when fibrosis disrupts the normal architecture of the liver resulting in liver dysfunction. Nodules are characteristic of disruption of parenchymal disruption.
New blood vessels [angiogenesis] are produced in the fibrous sheath surrounding the nodules. These vessels connect the hepatic artery and portal vein to hepatic venules, restoring the intrahepatic circulatory pathways.
This does provide a low-volume, high-pressure venous drainage but is unable to accommodate as normal blood volume as normal. This leads to an increase in portal vein pressure and contributes to portal hypertension.
The progression rate from fibrosis to cirrhosis vary from person to person.
Complications and Manifestations
Portal Hypertension
Normally, the liver can accommodate a large range of blood flow without affecting portal pressure. Increased portal venous inflow and increased resistance to portal blood flow are the main contributing factors
The high venous pressure gradient is defined as the difference in pressure between the portal vein and the inferior vena cava.
Portal hypertension is defined as a sustained elevation of portal pressure above normal.
Portal hypertension can cause the following problems further like esophageal, gastric, or rectal varices which could bleed spontaneously. It also causes portal hypertensive gastropathy.
Portal hypertension is the most common serious complication of cirrhosis. Ascites, hepatorenal syndrome, pulmonary hypertension, and hepatopulmonary syndrome occur because of portal hypertension.
Ascites
Ascites, which is an accumulation of excessive fluid within the peritoneal cavity, can be a complication of either hepatic or nonhepatic disease.
In cirrhosis, ascites is caused by a combination of elevated pressure in the veins running through the liver (portal hypertension) and a decrease in liver function due to fibrosis.
Typically, the ascites is transudative.
The presence of ascites in cirrhosis is a risk factor for spontaneous bacterial peritonitis.
Hepatorenal Syndrome
It is a kind of acute renal injury. Hepatorenal syndrome is caused by constriction of large and small renal arteries leading to impaired renal perfusion.
Hepatic Encephalopathy
Hepatic encephalopathy occurs in some patients with cirrhosis. It is marked by behavior and personality changes, cognitive impairment, and decreased the level of consciousness. It occurs when there is a diversion of portal blood into the systemic circulation.
The exact mechanism is not clear but the passage of toxins [short-chain fatty acids, mercaptans, false neurotransmitters] to the brain through the permeable blood-brain barrier.
Based on symptoms encephalopathy is graded as
- 1: Sleep disturbances; impaired concentration; depression, anxiety, or irritability
- 2: Drowsiness, disorientation, poor short-term memory, uninhibited behavior
- 3: Somnolence; confusion; amnesia; anger, paranoia, or other bizarre behavior
- 4: Coma
Encephalopathy grades are used in score calculation of cirrhosis
Other manifestations
- Anemia
- Decrease in platelet count [thrombocytopenia]
- Splenomegaly
- Decreased levels of thrombopoietin.
- Coagulopathy
- Decreased production of coagulation factors.
- Hepatopulmonary syndrome
- Arteriovenous shunting.
- Progressive and life-threatening
- Symptom of platypnea and orthodeoxia [dyspnea and hypoxia when upright, improves on lying down
- Portopulmonary hypertension
- Mean pulmonary artery pressure of> 25 mm Hg
- Hepatocellular carcinoma
- Cholangiocarcinoma
- Malnutrition
- Malabsorption of fat occurs because of less bile production.
- This also causes malabsorption of fat-soluble vitamins. Vit D malabsorption may contribute to osteoporosis.
Increased incidence of peptic ulcer disease, diabetes, and gallstones is found.
Histopathology Features of Cirrhosis
The liver is firm, has a gritty feel on cutting and the cut surface shows fibrous bands surrounding nodules of various sizes. Microscopic examination shows necrosis, collapse, fibrosis, regeneration, and altered circulation. Regenerating nodules, by compressing the blood supply of the liver cause ischemic damage of the liver even after the disappearance of the primary cause of liver injury.
Read more about Light Microscope: Parts, Usage, Handling and Care
Read more about Electron Microscope: Types, Uses, and Advantages
Cirrhosis can be
- Micronodular
- Nodules < 3 mm in diameter
- Thick regular bands of connective tissue
- Nodules lack lobular organization
- Early in the course
- Macronodular
- The nodules vary in size from 3 mm to 5 cm
- Have some relatively normal lobular organization of portal triads and terminal hepatic venules
- Broad fibrous bands surround the large nodules
Mixed cirrhosis has both micronodular and macronodular cirrhosis.
Staging of Cirrhosis
Child-Turcotte-Pugh score
This score is calculated by assigning points to various parameters. The points assigned depend on the severity or value of the parameter measured.
Child Turcotte Pugh score may predict life expectancy in patients with advanced cirrhosis. A score of 10 or greater is associated with a 50% chance of death within 1 year.
| Clinical Factor | Severity | Points |
| Encephalopathy grade | None | 1 |
| 1–2 | 2 | |
| 3–4 | 3 | |
| Ascites | None | 1 |
| Mild (or controlled by diuretics) | 2 | |
| At least moderate despite diuretic treatment | 3 | |
| Albumin (g/dL) | > 3.5 | 1 |
| 2.8–3.5 | 2 | |
| < 2.8 | 3 | |
| Bilirubin (mg/dL) | < 2 | 1 |
| 2–3 | 2 | |
| > 3 | 3 | |
| PT (seconds prolonged) | < 4 | 1 |
| 4–6 | 2 | |
| > 6 | 3 | |
| or, instead of PT | ||
| INR | <1.7 | 1 |
| 1.7–2.3 | 2 | |
| > 2.3 | 3 | |
MELD scoring system [for persons older than 12 years]
For children younger than 12 years, a different system is used which called PELD or pediatric end-stage liver disease.
This soring system is used by transplant surgeons and is called Model for End-Stage Liver Disease (MELD) scoring system. This assesses the relative severity of patients’ liver disease.
MELD uses the values of
- serum bilirubin
- serum creatinine,
- INR [international normalized ratio for prothrombin time]
MELD scrore is calculated by the following formula
MELD = 9.57 × loge(creatinine) + 3.78 × Loge(total bilirubin) + 11.2 × Loge(INR) + 6.43.
Online calculators are available for calculation of MELD score.
MELD is able to predict mortality. For example, a MELD score less than 9 has about 3% mortality at 3 months but same figure goes as high as 80% when score is greater than 40
Clinical Features
Cirrhosis could remain without symptoms for years. In fact, one-third of the patients are known to never develop the symptoms.
Earlier symptoms are often nonspecific
- Generalized fatigue
- Anorexia
- Malaise
- Weight loss
- Other features
- Muscle wasting
- Palmar erythema
- Parotid gland enlargement
- White nails Clubbing
- Dupuytren contracture
- Spider angiomas (< 10 may be normal)
- Gynecomastia
- Axillary hair loss
- Testicular atrophy
- Peripheral neuropathy.
Once any complication of cirrhosis develops, additional decompensation is much more likely.
Cirrhosis of liver may progress for years before any clinical suspicion is aroused because even 10 percent of healthy liver tissue is adequate for metabolic functions and liver tissue has a remarkable capacity to regenerate. The presenting features of cirrhosis are ascites, edema, hematemesis or hepatic coma. The clinical features can be classified as those due to liver cell failure and those due to portal hypertension.
Due to Liver cell failure:
- Palmar erythema, spider nevi
- Gynaecomastia, testicular atrophy and loss of libido
- Jaundice-usually mild, maybe severe terminally
- Ascites, edema and scrotal swelling
- Flapping tremors
- Alopecia
- Parotid swelling, Dupuytren’s contracture
- Wasting
Due to Portal Hypertension
- Splenomegaly and hypersplenism
- Dilated veins over the chest wall
- Hematemesis, melena and bleeding per rectum
- Ascites
Few manifestations and their causes are given below
- Abdominal distention – ascites
- Abdominal discomfort with fever or hepatic encephalopathy- Spontaneous bacterial peritonitis
- Calf pain or swelling, pulmonary embolism – Thromboembolism
- Clubbing- Hepatopulmonary syndrome
- Confusion, lethargy – Hepatic encephalopathy
- Dyspnea, hypoxia – Hepatopulmonary syndrome, Portopulmonary hypertension
- Fatigue – Anemia
- Fluid overload, oliguria – Hepatorenal syndrome
- Fragility fracture or insufficiency fracture – osteoporosis
- Infection – Leukopenia
- Jaundice – Cholestasis
- Petechiae, purpura, bleeding – Thrombocytopenia, Coagulopathy [decreassed synthesis in the liver]
- Itching, xanthelasmas- Cholestasis
- Rectal bleeding – Rectal varices
- Splenomegaly – Portal hypertension
- Steatorrhea – Fat malabsorption
- Upper GI bleeding – Esophageal varices
- Portal hypertensive gastropathy
Hernia may occur in ascites.
Lab Studies
Before we move to work up, here is a list of lab parameters that are affected.
- Aminotransferases – AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis.
- Alkaline phosphatase – usually slightly elevated.
- GGT – correlates with alkaline phosphatase levels. Typically much higher in chronic liver disease from alcohol.
- Bilirubin – may elevate as cirrhosis progresses.
- Albumin – levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver
- Prothrombin time – increases since the liver synthesizes clotting factors.
- Globulins – increased due to shunting of bacterial antigens away from the liver to lymphoid tissue.
- Serum sodium – hyponatremia due to the inability to excrete free water resulting from high levels of ADH and aldosterone.
- Thrombocytopenia – due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However, this rarely results in platelet count < 50,000/mL.
- Leukopenia and neutropenia – due to splenomegaly with splenic margination.
- Coagulation defects – the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.
Read more about Liver Function Tests
Imaging
Though not very sensitive, Ultrasound and MRI can help in detection of early cirrhosis before portal hypertension becomes evident.
Ultrasonography also detects portal hypertension and ascites when present.
CT is able to show nodular texture but has got no disadvantage over ultrasonography. The technetium-99m sulfur colloid scan shows irregular liver uptake. There are increased spleen and bone marrow uptakes too.
Identification of the cause
Determining the specific cause of cirrhosis requires key clinical information from the history and examination, as well as selective testing.
Collaborating Clinical Features and Workup – Finding the Cause
- Alcoholism
- Documented history
- Gynecomastia, spider angiomas (telangiectasia), and testicular atrophy
- AST [aspartate transaminase] elevated more than alanine transaminase [ALT]
- Highly increased gamma-glutamyl transferase
- Viral Hepatitis
- Presence of specific viral markers depending on virus type
- Autoimmune hepatitis
- High antinuclear antibody titer
- Hypergammaglobulinemia
- Anti–smooth muscle or anti-liver/kidney microsomal type 1 antibodies)
- Hemochromatosis
- Increased serum iron
- Transferrin saturation
- Genetic testing cues
- Alpha-1 antitrypsin deficiency
- Low serum alpha-1 antitrypsin level and genotyping
These are the major prevalent causes and should be sought first. If not, then other causes are sought.
If these causes are not confirmed, other causes are sought. Few points are that could guide in some cases are
- Antimitochondrial antibodies presence suggests primary biliary cholangitis.
- Strictures and dilations of the intrahepatic and extrahepatic bile ducts on MRI – Primary sclerosing cholangitis.
- Decreased serum ceruloplasmin – Wilson disease.
- Obesity and diabetes – Nonalcoholic steatohepatitis (NASH).
Role of Liver Biopsy in Cirrhosis
A biopsy is done when clinical features and tests are not conclusive.
For example, when it is suspected that cirrhosis is present and is well compensated but imaging studies are not helpful, biopsy should be done to confirm the diagnosis.
But a biopsy is not done in obvious cases of cirrhosis portal hypertension, ascites, and liver failure.
Read more about Liver Biopsy-Types, Indications, and Procedure
Read more about Types of Biopsies and Their Applications
Treatment
If a disease is identified before the onset of cirrhosis, specific medical treatment can diminish symptoms and even prevent or slow the development of cirrhosis.
The examples of this are
- Prednisone and azathioprine for autoimmune hepatitis
- Antiviral therapy for hepatitis B and C
- Phlebotomy for hemochromatosis
- Ursodeoxycholic acid for primary biliary cirrhosis
- Trientine [a chelating agent]
- Zinc for Wilson disease.
Once cirrhosis develops, the treatment for causative factors may continue. The treatment of cirrhosis is mainly supportive and management of complications. It includes
- Stopping substances causing injury
- Drugs
- Hepatotoxic substances
- Alcohol
- Good nutrition
- Vitamin supplementation
- Treatment of underlying disorders
- Drugs
- Zinc supplements for deficiency
- Stimulate appetite and eases dysgeusia [distortion of the sense of taste]
- Cholestyramine, antihistamines and ammonium lactate skin cream for pruritus
- Bisphosphonate for osteoporosis.
- Vaccination against hepatitis A
- Avoiding hepatotoxic drugs
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Isoniazid
- Valproic acid
- Erythromycin
- Amoxicillin-clavulanate
- Ketoconazole
- Chlorpromazine
- Ezetimibe
- Statins
- Variceal treatment to prevent bleeding
- Beta-blockers, and /or banding for esophageal
- Endoscopic banding balloon-occluded retrograde transvenous obliteration or endoscopic cyanoacrylate injection for stomach
- Transjugular intrahepatic portosystemic shunting (TIPS) in ascites and recurrent variceal bleeding.
- Liver transplantation for end-stage liver disease or hepatocellular carcinoma.
Follow-up and Monitoring
Esophageal varices
- First diagnostic endoscopy establishes the presence or absence of varices
- Absent – 2 yearly follow up with endoscopy
- Present
- Small size – follow up
- Moderate size
- Non-selective beta blocker
- Frequent endoscopic monitoring
- Large size – Banding
Surveillance for hepatocellular carcinoma
Ultrasonography every 6 months.
Video on Cirrhosis
References
- Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014 May 17. 383 (9930):1749-61.
- Gines P, Quintero E, Arroyo V, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987 Jan-Feb. 7(1):122-8.
- Angeli P, Fasolato S, Mazza E, et al. Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial. Gut. 2010 Jan. 59(1):98-104.
- Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology. 2007 Sep. 133(3):825-34.
- O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol. 2010 Jan. 105(1):14-32; quiz 33.