Chronic Liver Disease

Etiology

The following are the most common etiologies:

Alcoholic Liver Disease

Alcoholic liver disease is a spectrum of disease which includes alcoholic fatty liver with or without hepatitis, alcohol hepatitis (reversible because of acute ingestion) to cirrhosis (irreversible). Patients with severe alcohol use disorder mostly develop chronic liver disease; this is the most frequent cause of CLD.

Non-alcoholic Fatty Liver Disease (NAFLD/NASH)

NAFLD has an association with metabolic syndrome (obesity, hyperlipidemia, and diabetes mellitus). Some of these patients develop non-alcoholic steatohepatitis, which leads to fibrosis of the liver. All the risk factors of metabolic syndrome can aggravate the disease process.

Chronic Viral Hepatitis

Chronic hepatitis B, C, and D infections are the most common causes of chronic liver disease in East Asia and Sub-Saharan Africa. There are various genotypes of hepatitis C. In Europe and North America, genotype 1a and 1b are more prevalent, while in Southeast Asia, genotype 3 is more common. A molecular epidemiological study revealed a high prevalence of HCV genotype 4, subtype 4a among Egyptian patients living in Sharkia governorate, Egypt. Chronic hepatitis C, if not treated, may lead to hepatocellular carcinoma.

Genetic Causes

• Alpha-1 antitrypsin deficiency: This is the most common genetic cause of CLD among children.
• Hereditary hemochromatosis: It is an autosomal recessive disorder of iron absorption. Here due to a mutation involving the HFE gene that regulates the iron absorption from the intestine, excessive iron is absorbed from the gastrointestinal tract. As a result, there is a pathological increase in total body iron (such as ferritin and hemosiderin). This process leads to the generation of hydroxyl free radicals, which in turn causes organ fibrosis.
• Wilson disease: Autosomal recessive disorder leading to copper accumulation

Autoimmune Causes

Autoimmune hepatitis is a rare disease in which there is the destruction of liver parenchyma by autoantibodies. Most of the patients who present with this disease have already developed cirrhosis. Females are more commonly affected than males.

• Primary biliary cirrhosis (PBC): This is an autoimmune and progressive disease of the liver, which is the destruction of intrahepatic biliary channels and portal inflammation and scarring. It leads to cholestatic jaundice and fibrosis of liver parenchyma. PBC is more common in middle-aged women. Alkaline phosphatase levels increase in PBC.
• Primary Sclerosing Cholangitis (PSC): commonly associated with ulcerative colitis. This condition is characterized by a decrease in the size of intrahepatic and extrahepatic bile ducts due to inflammation and fibrosis. 
• Autoimmune hepatitis (AIH): This is a form of chronic inflammatory hepatitis, more common in women than men, and is characterized by elevated autoantibodies such as antinuclear antibodies, anti-smooth muscle antibodies, and hypergammaglobulinemia. 

Other Causes of Chronic Liver Disease

• Drugs - amiodarone, isoniazid, methotrexate, phenytoin, nitrofurantoin.
• Vascular. Budd-Chiari syndrome.
• Idiopathic/cryptogenic, around 15%

Epidemiology

Chronic liver disease is one of the frequent causes of death, especially in the developing world. The increasing prevalence of chronic liver disease has been noted in recent times. The majority of chronic liver diseases in the developed world include alcoholic liver disease, chronic viral hepatitis, including hepatitis B and C, non-alcoholic fatty liver disease (NAFLD), and hemochromatosis.[1] In the United States, according to the National Vital Statistics Report 2017 from the Center for Disease Control and Prevention, approximately 4.5 million adults had chronic liver disease and cirrhosis, which is 1.8 percent of the adult population. There were 41,473 deaths (12.8 deaths per 100,000 population) from chronic liver disease and cirrhosis. 

Pathophysiology

Chronic liver disease represents a continuous and progressive process of hepatic fibrosis, liver tissue architectural distortion, and regeneration nodule formation. While fibrosis is usually irreversible, but it can be reversible in the initial stage of development. The transition time point of reversible fibrosis to irreversible fibrosis is still not completely understood. In chronic liver disease, if not treated, the endpoint is usually irreversible fibrosis, regeneration nodule formation, and development of cirrhosis liver. The development rate of fibrosis is dependent on the underlying etiologies, environmental, and host factors. The evolution of liver fibrosis was studied in 4852 patients with different underlying etiology in one study. The author observed significant differences in the rate of development of fibrosis and its progression. The rate was most rapid in patients with coinfection with HIV- HCV, while primary biliary cirrhosis was the slowest. Fibrosis progression rate was higher with increasing age, and females demonstrated a more gradual progression of liver fibrosis in all but alcoholic liver disease.[2] Similarly, in another study, genetic polymorphism was attributed as an underlying factor for the difference in fibrosis rate progressions and the development of more severe disease in some individuals compared to others with the same underlying etiology.[3]

Hepatic fibrosis is the deposition of extracellular matrix (ECM) in response to chronic liver injury by any etiology. The common pathway is initiated by hepatic stellate cells (HSC), which usually are vitamin A storing dormant cells found in space between sinusoids and hepatocytes. In response to chronic liver injury, HSC gets activated into proliferative fibrogenic myofibroblast and upregulates the expression of inflammatory receptors such as chemokine receptors, ICAM-1, and other inflammatory mediators by releasing chemokines and other leukocyte chemoattractants. This pro-inflammatory phase or initiation phase also changes gene and phenotypic expression of the liver cells, making them more responsive to these inflammatory cytokines, and perpetuation of activated HSC cells results in the accumulation of ECM and progressive fibrosis.[4]

Histopathology

The stellate cells are thought to be the source of collagen in pathological conditions. Chronic liver injury activates hepatic stellate cells, which are activated and transformed into a myofibroblast-like phenotype. They then lay down the extracellular matrix. Chronic inflammation, cytokine production by damaged parenchymal cells, and disruption of the extracellular matrix are well-characterized stimuli to stellate cells. 

The etiology affects the patterns of liver fibrosis. Chronic hepatotropic virus infection causes portal expansion followed by periportal fibrosis, septal (bridging) fibrosis, and cirrhosis. Alcoholic liver disease and adult non-alcoholic fatty liver disease cause fibrosis, starting with a centrilobular perivenular distribution and sinusoidal fibrosis. Pediatric fatty liver disease is similar to hepatotropic virus infection with a periportal distribution. Perisinusoidal or perivenular fibrosis is usually not apparent.

Biliary tract disease cirrhosis is characterized by feathery degeneration of periseptal hepatocyte leasing to the presence of prominent “halos” and irregular-shaped nodules (“jigsaw” micronodular pattern). Fibrosis progressively links the adjacent central veins and portal tracts in venous outflow obstruction, resulting inveno-portal cirrhosis or veno-centric (“reversed lobulation” cirrhosis).[5]

History and Physical

Clinical Manifestations

Signs and symptoms of CLD can be nonspecific, such as fatigue, anorexia, weight loss, or depend upon the complication that the patient has developed. The three significant complications are because of portal hypertension (esophageal varices, ascites), hepatocellular insufficiency (e.g., jaundice, hepatic encephalopathy), and hepatocellular carcinoma. Decompensated chronic liver disease can present with one of the following complications.

Portal Hypertension

Portal hypertension is a result of resistance to portal blood flow because of cirrhotic and noncirrhotic etiology. A portal venous pressure above seven mmHg is considered portal hypertension; however, clinical features or complications do not develop until portal pressure is higher than 12 mmHg. Portal hypertension causes can divide into prehepatic (e.g., portal vein thrombosis), hepatic (e.g., cirrhosis), and post hepatic (e.g., Budd Chiari syndrome). Cirrhosis and hepatic schistosomiasis remain the most common cause of portal hypertension, with cirrhosis being more common in developed countries. The following are the consequences of long-standing portal hypertension.

• Esophageal varices: It presents with melena or upper GI bleed. Cirrhosis of the liver leads to raised portal pressure, which can cause esophageal or gastric varices. Esophageal variceal bleeding is the most common life-threatening complication of CLD.
• Caput medusae
• Rectal hemorrhoids
• Ascites: It is an accumulation of fluid in the peritoneal cavity because of raised portal pressure (increased hydrostatic pressure), decreased albumin (reduced oncotic pressure), and splanchnic vasodilation (due to the release of nitric oxide). Most of the patients develop ascites in the later stages of cirrhosis. Clinical findings in such patients are abdominal distension, shifting dullness, and a fluid wave. Tense ascites can lead to shortness of breath or early satiety.

Hepatocellular Insufficiency

Hepatic Encephalopathy

This is a neuropsychiatric syndrome caused by hepatic dysfunction. Detoxification of harmful products of metabolism, e.g., ammonia, occurs in the liver. In a patient with cirrhosis, the removal of these substances from the body is impaired, leading to an increased level of ammonia. Raised levels of ammonia can impair consciousness. Almost 50% of patients with DCLD can develop hepatic encephalopathy. 

According to AASLD guidelines, depending upon the severity of the disease, there are different grades of hepatic encephalopathy.[6]

• Grade 0/Minimal: Subclinical, normal mental status with minimal changes in memory, coordination, intellectual function, concentration.
• Grade 1: Trivial lack of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction, altered sleep rhythm.
• Grade 2: Lethargy or apathy, disorientation to time, personality change, inappropriate behavior, dyspraxia, asterixis.
• Grade 3: Somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behavior.
• Grade 4: Coma

The patient can present in any of these symptoms. Most of the patients with hepatic encephalopathy present with altered sensorium. Infections, GI bleed, hyperkalemia, TIPS[7], sedating agents, and alkalosis can aggravate hepatic encephalopathy.

Jaundice

Jaundice is a yellowish discoloration of the eyes, skin, and mucous membrane because of overproduction or under clearance of bilirubin. Metabolism of hemoglobin or myoglobin produces bilirubin in the spleen. Bilirubin then circulates in the body, bound to albumin. The liver dissociates this complex and converts unconjugated bilirubin to conjugated bilirubin. Jaundice is clinically visible when total bilirubin is greater than 2 mg/dl. As in chronic liver disease, there is the destruction of liver parenchyma, and it does not conjugate bilirubin, which deposits in various tissues of the body. There is pruritus because of the accumulation of bile salts.

Spontaneous Bacterial Peritonitis (SBP)

It is one of the acute and painful complications of chronic liver disease. Bacteria (E. coli, Klebsiella, Streptococcus pneumonia) seep through the gastrointestinal tract and infect the ascitic fluid. The infection spread through the fluid to the peritoneal membrane, causing inflammation. SBP presents with fever, generalized abdominal pain, tenderness, and absent bowel sounds.

Hyperestrinism

In chronic liver disease, the catabolism of estrogen becomes impaired, resulting in excess estrogen in the body. This manifests as palmar erythema, spider angiomas (dilated cutaneous arterioles with a central red spot and red extensions that radiate outward like a spider's web in the territory of SVC), gynecomastia (enlarged tender subareolar tissue), and testicular atrophy.

Hepatorenal Syndrome (HRS)

Hepatorenal syndrome is a functional renal failure as kidneys are normal, where there is a gradual loss of renal function. It is a diagnosis of exclusion. Vasoconstrictors are released in CLD, which is responsible for the narrowing of renal vessels. The following criteria have been described:

• Chronic liver disease with portal hypertension or advanced liver failure
• Continuous rising in creatinine, usually more than 0.3 mg/dl within 48 hours or doubling from baseline within seven days. 
• Oliguria with the absence  or minimal proteinuria
• Urine sodium less than 10 meq/L
• Failure to improve with volume expansion and stopping the diuretics.
• Absence of shock
• No recent use of the nephrotoxic drug
• Absence of renal parenchymal disease

Coagulopathy

The liver produces clotting factors, so the patients with CLD have coagulopathies and manifest or contribute to easy bruising and bleeding per gastrointestinal tracts. Hence, PT/INR (intrinsic pathway) and APTT (extrinsic pathways) are prolonged.

Evaluation

The diagnosis of chronic liver disease depends upon the etiology and complications of the disease. An outline regarding the diagnosis for various CLD appears below.

• Viral hepatitis B and C: Serology, PCR (quantitative and qualitative) with genotype
• Alcoholic liver disease: Elevated levels of AST>ALT with a history of chronic alcohol intake. Usually, AST: ALT ratio is 2 to 1 in alcoholic liver disease.
• Hemochromatosis: Raised serum iron, ferritin, decreased TIBC, and liver biopsy. Genetic testing can detect a mutation in the HFE gene, especially C282Y.
• Wilson disease: Raised urine copper, decreased serum ceruloplasmin, and liver biopsy. Genetic testing for the ATP7B gene.
• Non-alcoholic fatty liver disease: Diagnosis of exclusion and ALT>AST. Ultrasonography of the liver is informative. 
• Autoimmune hepatitis: Raised ANA, ASMA, and LKM-1
• Alpha 1 antitrypsin deficiency: Decreased levels of alpha one antitrypsin
• Primary biliary cirrhosis: Markedly raised alkaline phosphatase levels with an antimitochondrial antibody
• Budd-Chiari and veno-occlusive disease: CBC, clotting profile, and imaging studies like ultrasound doppler or computed tomography with contrast study

 Laboratory Findings

In chronic liver disease, there is inflammation and destruction of hepatocytes that leads to the release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), hence the high levels of these markers in the blood. Other parameters (ALP and GGT) of LFTs also appear elevated in cholestatic conditions like PBC. AST and ALT are usually elevated two to three times of normal limit, but normal levels of these markers do not rule out cirrhosis.[8] As in compensated CLD LFTs may be normal in cirrhosis. Bilirubin (unconjugated> conjugated) levels are elevated in jaundice. There is reduced production of clotting factors leading to raised PT/INR and APTT.

Because of hepatocellular insufficiency in cirrhosis, albumin level drops, and ammonia raises, causing ascites and hepatic encephalopathy. The increased concentration of ammonia, tryptophan metabolites, short-chain fatty acids, octopamine, mercaptans, increased oxidative stress, and increase intracellular osmolality are among many which have been proposed as the mechanism of developing hepatic encephalopathy.[9][10][11][12][13] In the case of ascites, diagnostic paracentesis is an investigation of choice to see whether ascites are because of raised portal pressure or another cause. By doing a biochemical and cytological analysis of ascitic fluid, we calculate the serum ascites albumin gradient (serum albumin-ascitic fluid albumin). If this gradient is greater than 1.1, then portal hypertension is a likely cause, but if it is less than 1.1, portal hypertension is unlikely. WBC greater than 500/microliter or PMN greater than 250/microliter and fluid cultures will be positive in patients with SBP.[14] Ultrasound of the abdomen and serum AFP levels can help diagnose the presence of hepatocellular carcinoma. In hepatorenal syndrome, creatinine usually is elevated to more than1.5 g/dl. Thrombocytopenia is an indirect measure of splenomegaly, which occurs in CLD because of raised portal pressure.

Radiologic Investigations

It includes an abdominal ultrasound, CT scan, fibro scan, hepatic wedge pressure, endoscopy, EEG, TIPS, triphasic CT, and Doppler scan.

• Ultrasound abdomen is one of the most common and affordable imaging studies in the case of chronic liver disease. Ultrasound detects the size, echogenicity nodularity of the liver, thereby diagnosing liver cirrhosis. Other benefits of ultrasound in CLD include measurement of portal vein diameter as portal vein diameter increases in portal HTN and assessment of a clot in the hepatic vein (Budd-Chari) and portal vein in portal vein thrombosis.
• Computed tomography scan can show a lesion in the liver or obstruction of biliary channels in a more precise way, but triphasic CT is the test of choice in diagnosing hepatocellular carcinoma. 
• Transient elastography (TE) detects early stages of cirrhosis. It can also detect cardiovascular damage in patients with NAFLD.[15] It works on two physical principles; strain displacement and shear wave imaging and quantification. The latter includes point shear wave elastography. It measures the velocity of low frequency (50 Hz) elastic shear waves propagating through the liver. The stiffer the tissue, the faster the elastic shear wave propagates. It can easily work on an ultrasound machine. According to the European association of study for the Liver (EASL), TE is the most effective approach to diagnose cirrhosis in chronic liver disease.
• Wedge hepatic venous pressure measures portal venous pressure in CLD.
• Doppler scan can help in diagnosing Budd-Chiari and portal vein thrombosis.
• EEG shows delta waves in hepatic encephalopathy.
• An upper endoscopy can diagnose and treat esophageal varices. On endoscopy, we can measure the size of varices. Small varices are less than 5 mm, and large varices are greater than 5 mm.
• A liver biopsy can confirm the diagnosis of chronic liver disease. Various techniques to perform a liver biopsy are by laparoscope, transjugular, or percutaneously.

Treatment / Management

Treatment and Prophylaxis

The treatment goal is to stop the progression of the disease and complications and require a multidisciplinary approach. The principle of management is mainly underlying cause correction, Portal hypertension management, and specific treatments for individual disease. A brief outline regarding treatment for various CLD and related complications is given below. For more comprehensive details, please see individual topics in the Statpearls glossary.

General Management

Patients with chronic liver disease mostly present with one of the complications.

Esophageal varices - Varices related bleeding are one of the deadly complications, and the treatment includes aggressive fluid resuscitation, vasopressors (octreotide, terlipressin), and endoscopy. Endoscopic band ligation and injection sclerotherapy are the usual modalities to treat variceal bleed in an emergency. In some patients, early transjugular intrahepatic portosystemic shunt (TIPS) can increase the survival rate. Propranolol is used for primary and secondary prophylaxis for esophageal varices. Diuretics (furosemide, spironolactone) and sodium restriction are essential treatment options for ascites. For tense ascites, therapeutic paracentesis is done. Albumin infusion can also be considered. Initially, broad-spectrum antibiotics are the treatment of choice for SBP and then specific antibiotics after culture. 

Hepatic encephalopathy - The basic principle of treatment is to address the precipitating factors. Patients with hepatic encephalopathy usually improve with precipitating cause correction along with rifaximin and lactulose.[16][17] Lactulose acts by converting ammonia to ammonium ions and decreases its absorption from the gastrointestinal tract. Lactulose also relieves constipation through its osmotic effect, which further helps to ease the symptoms of hepatic encephalopathy. Rifaximin is used to decrease ammonia production by gut flora. Liver transplant is a curative treatment in patients with hepatorenal syndrome.(A1)

Hepatorenal syndrome - HRS based on severity divided into two categories. HRS 1 is more severe compared to HRS 2 (less severe). The primary goal is to correct underlying cause correction to reverse acute kidney injury. Treatment modalities depend on the severity and location of the patient. Treatment modalities include norepinephrine or terlipressin with albumin infusion or midodrine, octreotide with albumin infusion. TIPS procedure in some patients can help and liver transplantation the only definite treatment in the patient who fails to respond to all other treatments.[18][19][20]   (A1)

Hepatocellular carcinoma (HCC) - Treatment is based on the Barcelona clinic liver cancer staging system in the management of HCC:

• Initial stage (single HCC lesion): Resection and ablation.
• Intermediate stage: Transarterial chemoembolization and radio-embolization.[21]
• Metastatic disease: Sorafenib[22]

Specific Treatment

Viral Hepatitis

• Continuous viral suppression with nucleoside and nucleotide analogs 
• Direct-acting antivirals achieving HCV eradication 
• Interferon-alpha

Alcoholic liver disease: Alcohol abstinence

Non-alcoholic fatty liver disease: Treatment of metabolic syndrome components

Autoimmune hepatitis: Corticosteroids and other immunosuppressive drugs

Hereditary hemochromatosis: Phlebotomy, iron-chelators 

Copper overload (Wilson disease): Copper chelators 

Alpha-1-antitrypsin deficiency: Transplant

Drugs and toxins: Identify and stop the factor

Primary biliary cholangitis (PBC): Ursodeoxycholic acid (UDCA)[23] (A1)

Primary sclerosing cholangitis: Transplant

Budd-Chiari syndrome: Anticoagulation, thrombolysis or angioplasty with or without stenting, TIPS, or liver transplant

Differential Diagnosis

• Constrictive pericarditis
• Cor-pulmonale
• Dilated cardiomyopathy
• Inferior vena cava thrombosis
• Nodular regenerative hyperplasia
• Sarcoidosis
• Schistosomiasis

Staging

Stages of liver disease

1. Hepatitis or steatosis or hepatosteatosis
2. Fibrosis
3. Cirrhosis
4. Hepatocellular carcinoma (HCC)

Prognosis

Compensated chronic liver disease (who has not developed significant complications) usually carries a better prognosis than decompensated liver cirrhosis. Decompensated liver cirrhosis patients (who have developed variceal bleeding, ascites, HCC, SBP, and hepatorenal syndrome) have a poor prognosis. Mean survival of about six months if Child-Pugh score of 12 or greater or MELD score of 21 or higher.

There are various scoring systems used to assess the severity of chronic liver disease.

1. The Child-Pugh score uses ascites, bilirubin, albumin, PT, and encephalopathy.

• Class A (score 5-6): well-compensated disease.
• Class B (score 7-9): functional compromise.
• Class C (score 10-15): decompensated disease.

2. MELD (model of end-stage liver disease) uses bilirubin, serum creatinine, and INR. The MELD score was initially used to predict mortality within three months after the TIPS procedure and now used to prioritize patients for receipt of a liver transplant.

Complications

The following are the complications of chronic liver disease.

• Variceal bleeding
• Ascites and spontaneous bacterial peritonitis (SBP)
• Hepatic encephalopathy
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Hepatocellular carcinoma (HCC)