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Cause of Cirrhosis Other Than Alcohol

Liver cirrhosis is a chronic liver disease distinguished by the degeneration of cells in the liver, causing fibrosis and malfunctioning regenerating nodules that lead to complications due to portal hypertension 1. In 2015, liver cirrhosis and liver neoplasms accounted for 3.5% of worldwide deaths 2. About 1 million annual deaths are accounted for by liver cirrhosis, making it the 11th cause of death and 4th in the cause of disability-adjusted lives worldwide 2. Cirrhosis is more prevalent in developing countries like Pakistan than in developed countries like Europe 1. Europe is prevalently the country with the most liver disease in the world, with about 26 cases per 100000 inhabitants 2. The major cause of cirrhosis in Europe is an alcoholic liver disease which causes about (9.2 deaths per 100,000) inhabitants, with hepatitis C virus (HCV) following with about (5.3 deaths per 100,000) inhabitants and thirdly hepatitis B virus (HBV) with( 3.9 per 100,000) inhabitants 2. However, in Pakistan, the Hepatitis C and Hepatitis B virus are the leading causes of cirrhosis respectively 1. A study in 2009 in Pakistan revealed that the most commonly affected age group was 40-60 years 1. With the severity and alarming rate of death caused by cirrhosis, there has been the invention of noninvasive biomarkers that investigate and predict the stages of liver fibrosis 3. This literature review aims at examining the different causes of liver cirrhosis other than alcohol.

Causes of liver cirrhosis other than alcohol

Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV)

HBV and HCV both may lead to increased morbidity and mortality in patients as a result of chronic liver infections that may cause liver cirrhosis, heap-tocellular carcinoma, and other liver cirrhosis complications 1. Hepatitis c virus often leads to more chronic stages than hepatitis B virus1 and similarly confer a greater risk of hepatocellular carcinoma than other causes 5. Out of the approximate 4.1 million people who showed a history of HCV exposure, 2.5 million resulted in chronic stages 4. A one-time HCV opt-out screening for individuals above 18 years is recommended 4. Early care and treatment of patients with chronic hepatitis C may prevent the progress to liver cirrhosis and the late stage of liver diseases 4. Due to the advancement and simplified management of hepatitis C, physicians can now follow up and provide treatment to more individuals 4. In healthy blood donors, HCV prevalence indicated a 15.6% in Africa, 0.34% in Canada, 1.5% in Japan, 0.64%in US, 0.075% in the United Kingdom, and 00-20.89% in Pakistan 4. Only about 15% of the HCV-infected patients are able to overcome the acute viral infection leaving about 85% being unable to control it 6. While the prevalence of HCV is 27.7%, only about 8% are carriers of HBV in developing countries 6.

Non-alcoholic fatty liver disease.

Non-alcoholic liver disease (NAFLD) is one of the major causes of liver cirrhosis and it affects about one-third of the western population 8. NAFLD is mainly characterized by the liver cells storing excessive fat 9. However, there are no proven facts as to why some individuals tend to have fat accumulate in the liver and others don’t 9. Similarly, little to no knowledge as to why some of the affected fatty livers lead to liver cirrhosis 9. Some of the patients with NAFD may acquire Nonalcoholic steatohepatitis (NASH), which is a belligerent result of fatty liver diseases9. NASH is characterized by inflammation of the liver and is likely to result in cirrhosis in some liver failure 9. Both NAFLD and NASH’s possible causes include obesity, insulin resistance, high levels of triglycerides fats in the blood, and hyperglycemia 9. According to findings from the University of Health Sciences, NAFLD is a major problem in obese adolescents due to decreased levels of omentin-1 8. Individuals with sleep apnea, metabolic syndrome, polycystic ovary syndrome, hypothyroidism, and hypopituitarism, are at risk of acquiring NAFLD9. Due to inflammation as a result of NASH, fibrosis occurs while the liver is trying to counteract the inflammation 9. As the inflammation continues, fibrosis spreads more in the liver tissues thus leading to cirrhosis 9. The risk of NASH and NAFLD progression to cirrhosis is between 5% and 12% 9.

Primary sclerosing cholangitis (PSC)

Primary sclerosing cholangitis (PSC) is a disease of the liver that is a result of continuous bile ducts inflammation and scarring 10. As a result, multifocal bile duct strictures are developed leading to fibrosis and later progressing to cirrhosis 11. Despite PSC not being a common disease, it has an incidence of 0.8 to 1.3 per 100000 persons 11. Although the PSC’s pathogenesis remains unknown, some evidence indicates that environmental, genetic, and immunologic factors are linked to it 11. PSC just like most diseases has variants, classic PSC which is the major cause of PSC cases is characterized by cholangiography strictures in the bile ducts 12. The large duct PSC which is predominant in males coexists with inflammatory bowel disease (IBD) and shows with cholestasis 12. Despite most PSC patients having IBD only 5% of IBD patients develop PSC 12. The small duct PSC patients, which is a small group, show a genetic link to PSC 12. PSC cure is yet to be determined and patients who advance to chronic liver disease and cirrhosis undergo liver transplantation11. Although PSC reoccurs in 23% of individuals after the liver transplantation11, in most cases it is curative. The development of antiviral therapies for other chronic liver diseases like hepatitis C triggered the research for PSC treatments which are currently ongoing 12.


Liver chemistries are used to determine the liver functions and identify any present diseases4. Liver enzymes, like alkaline phosphate (AP), are used to show the occurrence of hepatocellular damages or biliary obstruction4. Alanine aminotransferase (ALT) is more effective in determining liver injuries 4. Although aspartate aminotransferase also determines liver injuries, ALT is a better marker for the injuries 4.

Hepatitis C is the most common cause of liver cirrhosis worldwide after alcoholic liver disease 1. While injection of drug use is the main risk factor for HCV infections with over 60% case attributes4, other factors like hemodialysis, parenteral exposure, incarceration also are risk factors. HBV genotype D characterized by distinct viral characteristics is the main attribute for HBV13. The hepatitis B e antigen is mainly detected in its negative phase which results in chronic HBV 13. NAFLD is majorly linked to the metabolic rate and genetics of individuals. Obese adolescents are at a higher risk of contracting NAFLD due to excessive fat storage. For PSC more research is ongoing to determine its pathogenesis and relation to IBP12.

Newer investigations of the diagnosis of liver disease are ongoing due to the implicit disadvantage of liver biopsy being invasive hence making it difficult to assess repeated progressions 3. Non-invasive biomarkers are now being used to predict fibrosis stage3. These indirect markers are based on the effect of fibrogenic markers, unlike the direct fibrosis markers that rely on the basic mechanism of fibrosis3. Currently, Artificial intelligence (AI) is the most recent addition and it works by interpreting data from images with a convolutional neural network3. Additionally, the combination of the serological and radiographical methods while used stepwise could yield better results in the determination of chronic liver diseases including cirrhosis3.


  1. Ullah F, Khan S, Ayesha Khan Afridi, Sadiq Ur Rahman. Frequency of different causes of cirrhosis liver in local population. Gomal Journal of Medical Sciences. 2012 [accessed 2022 Feb 21]; 10(2).¤tPosition=1&docId=GALE%7CA320805212&docType=Clinical+report&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=1&contentSet=GALE%7CA320805212&searchId=R17&userGroupName=tel_a_utc&inPS=true
  2. Silva J, Silva M, Calinas F, Nogueira P. Burden of Liver Cirrhosis in Portugal between 2010 and 2017. GE – Portuguese Journal of Gastroenterology. 2020 [accessed 2022 Feb 21]; 28(3):153–161.¤tPosition=8&docId=GALE%7CA660853519&docType=Clinical+report&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=1&contentSet=GALE%7CA660853519&searchId=R11&userGroupName=tel_a_utc&inPS=true. Doi: 10.1159/000510729
  3. Wadhwa R, Aathira Ravindranath. Newer Investigations in the diagnosis of cirrhosis of liver. APIK Journal of Internal Medicine. 2022 [accessed 2022 Feb 21]; 10(1):1–1.¤tPosition=88&docId=GALE%7CA689195393&docType=Editorial&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=5&contentSet=GALE%7CA689195393&searchId=R9&userGroupName=tel_a_utc&inPS=true
  4. Baumgartner K, Cooper J, Smith A, Joshua St. Louis. Liver Disease. FP Essentials. 2021 [accessed 2022 Feb 21];(511):2–52.¤tPosition=1&docId=GALE%7CA687676828&docType=Article&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=1&contentSet=GALE%7CA687676828&searchId=R18&userGroupName=tel_a_utc&inPS=true
  5. Marot A, Henrion J, Knebel J-F, Moreno C, Deltenre P. Alcoholic liver disease confers a worse prognosis than HCV infection and non-alcoholic fatty liver disease among patients with cirrhosis: An observational study Strnad P, editor. PLOS ONE. 2017 [accessed 2022 Feb 22]; 12(10):e0186715.¤tPosition=1&docId=GALE%7CA511732629&docType=Report&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=1&contentSet=GALE%7CA511732629&searchId=R10&userGroupName=tel_a_utc&inPS=true. doi:10.1371/journal.pone.0186715
  6. Saeed U, Waheed Y, Ashraf M. Hepatitis B, and hepatitis C viruses: a review of viral genomes, viral-induced host immune responses, genotypic distributions, and worldwide epidemiology. Asian Pacific Journal of Tropical Disease. 2014 [accessed 2022 Feb 22]; 4(2):88–96. Doi: 10.1016/s2222-1808(14)60322-4
  7. UTC Central Authentication Service. 2022 [accessed 2022 Feb 22].¤tPosition=35&docId=GALE%7CA688443004&docType=Article&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=2&contentSet=GALE%7CA688443004&searchId=R18&userGroupName=tel_a_utc&inPS=true
  8. UTC Central Authentication Service. 2022 [accessed 2022 Feb 22].¤tPosition=35&docId=GALE%7CA688443004&docType=Article&sort=Relevance&contentSegment=ZHCC&prodId=HRCA&pageNum=2&contentSet=GALE%7CA688443004&searchId=R18&userGroupName=tel_a_utc&inPS=true
  9. Nonalcoholic fatty liver disease – symptoms and causes. Mayo Clinic. 2021 [accessed 2022 Feb 22].
  10. Primary Sclerosing Cholangitis (PSC) | Cedars-Sinai. 2021 [accessed 2022 Feb 22].,and%20starts%20to%20damage%20it.
  11. Sabino J, Vieira-Silva S, Machiels K, Joossens Felonylony G, Ballet V, Ferrante M, Van Assche G, Van der Merwe S, Vermeire S, et al. Primary sclerosing cholangitis characterized by intestinal symbiosis independent from IBD. Gut. 2016; 65(10):1681–1689. Doi: 10.1136/gutjnl-2015-311004. [Accessed 2022 Feb 22]
  12. UTC Central Authentication Service. [accessed 2022 Feb 22].
  13. Laras A, Papatheodoridi M, Panopoulou E, Papatheodoridis GV, Hadziyannis SJ, Hadziyannis E. Serum hepatitis B virus RNA detectability, composition and clinical significance in patients with ab initio hepatitis B e antigen negative chronic hepatitis B. Virology Journal. 2022 [accessed 2022 Feb 22]; 19(1).¤tPosition=2&docId=GALE%7CA693520135&docType=Article&sort=Relevance&contentSegment=ZHCE&prodId=HRCA&pageNum=1&contentSet=GALE%7CA693520135&searchId=R2&userGroupName=tel_a_utc&inPS=true. Doi: 10.1186/s12985-022-01749-7


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