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Cryptogenic Cirrhosis

Cryptogenic cirrhosis is a type of cirrhosis whose causes remain unknown. Cirrhosis, in general, is a chronic condition affecting the liver which causes scarring and extensive hepatic fibrosis


Presentation

Symptoms of cryptogenic cirrhosis are no different than the symptoms in any other type of cirrhosis: jaundice, abdominal swelling, weight loss, fever and blood in the stool are the predominant features. Before the liver has reached a cirrhotic stage, if the patient is affected by NASH, potential symptoms are non-specific and involve fatigue and weight loss.

Easy Bruising
  • Cirrhosis can lead to Easy bruising or bleeding, or nosebleeds Swelling of the abdomen or legs Extra sensitivity to medicines High blood pressure in the vein entering the liver Enlarged veins called varices in the esophagus and stomach.[icdlist.com]
  • Cirrhosis can cause weakness , loss of appetite , easy bruising , yellowing of the skin ( jaundice ), itching , and fatigue .[medicinenet.com]
  • Some of the more common symptoms and signs of cirrhosis include: Yellowing of the skin (jaundice) due to the accumulation of bilirubin in the blood Fatigue Weakness Loss of appetite Itching Easy bruising from decreased production of blood clotting factors[craigcameron.us]
Non-Alcoholic Cirrhosis
  • The last is obviously indicated for alcoholic cirrhosis, but in fact it is recommended for cryptogenic or non- alcoholic cirrhosis as well, because alcohol intake will certainly risk further damage even if alcohol is not the cause of the cirrhosis to[fattyliverdiseasecures.com]
  • […] due to cirrhosis Advanced cirrhosis Bacterial portal cirrhosis Capsular portal cirrhosis Cardiac cirrhosis Cardiac portal cirrhosis Cardituberculous cirrhosis Chronic hepatitis C with stage 3 fibrosis Chronic hepatitis c, stage 3 fibrosis Cirrhosis - non-alcoholic[icd9data.com]
Jaundice
  • Age, jaundice, spiders, palmar erythema and factor V showed a statistically significant difference of the cryptogenic cirrhosis when compared with both alcoholic and viral etiologies.[ncbi.nlm.nih.gov]
  • CARDIAC CIRRHOSIS Clinic a l featu r es · Mild jaundice · Liver dysfunction · Hepatomegaly – firm, non tender • *Ascites · Peripheral edema · Oesophageal bleeding · Encephalopathy.[medicscientist.com]
  • Cryptogenic Liver Cirrhosis Symptoms Symptoms include fatigue; substantial weight loss; jaundice; fever; swelling in the abdomen; and blood in stools.[livercirrhosiscurednaturally.com]
  • They include swelling and pain in the abdomen, fatigue, weakness, nausea, vomiting, loss of appetite, bloody stools, unexplained loss of weight, jaundice, rashes, and discoloration of the skin.[liverbasics.com]
  • […] surrounded by smaller vessel lesions (appearing in about 1/3 of cases); deformation of finger or toenails; mottling of the palm of the hand in speckles; inflammation of the periosteum of the long bones, which produces considerable pain; enlarged liver; jaundice[fattyliverdiseasecures.com]
Hepatomegaly
  • Diagnoses were based on histology in all but 3 patients (2 elderly women with liver atrophy and severe cirrhotic ascites diagnosed clinically with cryptogenic cirrhosis and 1 adult man with abnormal serum aminotransferase levels and hepatomegaly that[ncbi.nlm.nih.gov]
  • CARDIAC CIRRHOSIS Clinic a l featu r es · Mild jaundice · Liver dysfunction · Hepatomegaly – firm, non tender • *Ascites · Peripheral edema · Oesophageal bleeding · Encephalopathy.[medicscientist.com]
  • Elevations in liver enzymes and hepatomegaly have been described in patients treated with colchicine 34 , and liver damage in colchicine intoxication was also reported 18 .[journals.lww.com]
  • The hepatologist was requested to carefully go through a provided list of clinical stigmata of chronic liver disease and cirrhosis including spider angiomata, palmar erythema, finger clubbing, Dupuyetren’s contracture, gynecomastia, hepatomegaly, splenomegaly[omicsonline.org]
Neglect
  • […] disease progresses, other symptoms and complications may appear including bruising and bleeding, hepatic encephalopathy (a pathology of the brain resulting from liver dysfunction, causing changes in sleep habits, trouble concentrating, forgetfulness, or neglect[fattyliverdiseasecures.com]
  • We would suggest that, in recent studies addressing the interrelationship between T2DM and NAFLD, two major background variables are being neglected; the pervasive and obviously difficult to prove under- reported alcohol consumption and the newly emerged[omicsonline.org]

Workup

The diagnosis of cryptogenic cirrhosis is established by excluding other potential causes. A detailed medical history will help reveal underlying conditions such as diabetes, or a possible alcoholic habit, which could account for the condition. Furthermore, since certain drugs are known to cause cirrhosis, a physician should always inquire about intake of medications such as amiodarone, methyldopa, methotrexate etc.

NAFLD is also a condition that can lead to a cirrhotic liver and proper attention should be reserved for this possibility. Diagnosis is established with the aid of ultrasonography (US), computed tomography (CT) scans without contrast, an magnetic resonance imaging (MRI) scan and a liver biopsy. A typical CT scan will reveal a homogenous parenchyma with low density, MRI will illustrate bright areas representing fatty deposits and a US scan will display less specific findings, such as a normal echotexture and a bright parenchyma. Even though a liver biopsy is not performed in all cirrhosis candidates, due to possible complications (hemorrhage), and does present certain limitations depending on the location of the specimen, it remains as the gold standard for the definitive diagnosis [5] [6] [7] [8] [9] [10] [11] [12].

Another possibility that has to be excluded for cirrhosis to be defined as cryptogenic is the existence of an autoimmune hepatitis. A proper diagnostic approach involves the quantification of gammaglobulin levels, antinuclear antibodies, LKM1 antibodies and smooth muscle antibodies.

Non-invasive methods used to detect fibrosis

It is required to perform the following non-invasive procedures in cases of patients who run a high risk for NASH, in order to identify potential fibrosis:

  • Age >50: quantification of AST/ALT ratio, INR and platelet count.
  • Pre-existing diabetes mellitus: quantification of Retinol-Binding Protein 4 (RBP4), which is produced by adipocytes and preserved intrahepatically. Obesity leads to increased levels of RBP4, which is responsible for triggering an insulin resistance and contributing to the exacerbation of NASH.
  • Obesity (BMI ≥28 Kg/m2): Transient Elastography (Fibroscan), which assesses hepatic elasticity.
Enlargement of the Spleen
  • Enlargement of the spleen (splenomegaly). Portal hypertension can also cause changes to the spleen. Decreased white blood cells and platelets in your blood can be a sign of cirrhosis with portal hypertension. Bleeding.[mayoclinic.org]
  • Abdominal US revealed enlarged liver and spleen and the presence of peritoneal fluid.[journals.lww.com]
Globulins Increased
  • Serum globulin increases in cirrhosis and in most liver disorders with an inflammatory component. Anemia is common and usually normocytic with a high RBC distribution width.[merckmanuals.com]
Hepatocellular Carcinoma
  • Hepatocellular carcinoma was detected in 8 of 27 (27%) CC-O patients versus 21% of matched C-HCV controls with a similar age cumulated incidence, suggesting a comparable carcinogenic potential.[ncbi.nlm.nih.gov]
  • The lower occurrence of hepatocellular carcinoma and higher survival rate may indicate an indolent clinical course in CC as compared with viral cirrhosis.[ncbi.nlm.nih.gov]
  • We report a case of 53-year-old obese male, with known cryptogenic cirrhosis and hepatocellular carcinoma, presenting a tender mass on left breast. He was diagnosed with invasive intraductal carcinoma, which was consistent with a sporadic lesion.[ncbi.nlm.nih.gov]
  • There were no differences in gender, mean age of 47 years, average MELD (Model for End-stage Liver Disease) of 16, and hepatocellular carcinoma incidence (8%). In 28.6% of patients, the diagnosis of CC was wrong.[ncbi.nlm.nih.gov]
  • After using rigorous serologic and histopathologic screening guidelines, 20 patients were studied, 7 of whom had concurrent hepatocellular carcinoma (HCC).[ncbi.nlm.nih.gov]

Treatment

Therapeutic schemes applied in cirrhotic patients depend on the cause of the condition. The aim of all types of treatment is to address the underlying cause, relieve the patients from its symptoms, hinder its progression and stabilize the liver. For instance, corticosteroids and azathioprine are used to treat autoimmune hepatitis, interferons are used against viral hepatitis B and C and trientine is employed in cases of Wilson's disease.

Since cirrhosis is an irreversible and untreatable condition, therapy aims at symptom relief and  primarily targets the complications of cirrhosis. Patients who have developed ascites have to restrict sodium intake, use diuretics and may also be candidates for paracentesis and shunts. In cases of diagnosed hepatic encephalopathy, antibiotics and lactulose are administered. In order to definitively address the problem of cirrhosis, the only treatment option is a liver transplant; it is important to draw attention to the fact that patients with cirrhosis due to NASH will possibly exhibit fatty deposits in the transplanted liver as well.

Prognosis

Even though cirrhosis is an irreversible condition, its causes can be determined in 90% of the cases: hepatitis B and C, alcoholism, diabetes, and mechanical bile duct obstruction are some of the diseases which can lead to cirrhosis. If the causes are determined early and proper treatment is administered, the fibrosing and scarring phenomena are hindered and cirrhosis remains stable. In cases of cryptogenic cirrhosis, however, since the etiology remains unknown, patients are irrevocably led to a hepatic transplant as it is the only therapeutic option.

Etiology

By definition, cryptogenic cirrhosis is a condition for which no causes have been identified. The percentage of cirrhotic patients belonging in this category amounts to a 10%. Many of the cases which are termed as "cryptogenic" are in reality a result of an underlying condition known as non-alcoholic fatty liver disease or NAFLD. It is a disease characterized by fatty deposits on the liver, and NASH is its most extreme type. As the condition progresses, it leads to scarring and inflammation of hepatic tissue and the accumulation of fat (steatosis) sometimes subsides, rendering it difficult for NAFLD to be diagnosed; as a result, causes remain unknown.

Non-alcoholic fatty liver disease is triggered by many other conditions, including obesity, diabetes and hypertriglyceridemia [4]. In fact, diabetes and obesity can directly cause cirrhosis, without the onset of NASH, in some patients.

Epidemiology

With the modernization of diagnostic tools and the advancement of medical knowledge on hepatic conditions, cryptogenic cirrhosis cases have started to decline in numbers. It is estimated that only a 10% of the patients suffering from cirrhosis have a type which is deemed cryptogenic. The condition affects primarily individuals of the senior population, namely of over 60 years old.

Sex distribution
Age distribution

Pathophysiology

Scarring and fibrosis of the liver are both trademarks of a chronic, gradual hepatic condition that frequently result in cirrhosis. This is defined as an irreversible condition of the liver, also characterized by the formation of hepatocellular nodules. Fibrosis is, in fact, a direct result of the increased intrahepatic concentration of collagen (type I and III), which is produced by stellate cells. The extensive accumulation of collagen, both in the parenchymal regions and in the Disse space, leads to an imbalance of the exchange between the plasma and hepatic cells.

Cirrhosis has an important complication: portal hypertension, namely a substantial increase of the abdominal pressure, because of the hepatic incapacity to forward the blood from the portal vein to the inferior vena cava. Another significant problem caused by a cirrhotic liver is that the organ itself is subject to hypoperfusion.

The obstruction of blood flow due to a fibrosing liver alongside the destruction of hepatic cells, leads to a decreased protein synthesis, malnutrition and subsequent ascites. Furthermore, since the liver is responsible for the filtering of toxins, cirrhotic phenomena also lead to the accumulation of such by products in the organism, which find their way to the brain and lead to a condition called hepatic encephalopathy.

Prevention

Only comprehensive measures can be suggested for the avoidance of cryptogenic cirrhosis, since its causes are yet to be discovered. Any individual is advised to avoid risk factors such as alcohol and acetaminophen abuse, IV drugs, unprotected sexual intercourse and the use of non-sterilized syringes at any case. Anti-hepatitis A and B vaccines should also be administered, obesity should be avoided and any type of liver condition must be treated appropriately and consistently in order to avoid the onset of cirrhosis. Relatives of patients who exhibit cirrhosis due to hemochromatosis or Wilson's disease should be tested as well and blood donation must be carried out with extreme caution, so as to eliminate occasions of disease transmission.

Summary

Cirrhosis is a chronic, incurable hepatic condition which features characteristic fibrosing alterations and irregular hepatocellular nodules [1] [2]. Cases of cirrhosis are termed "cryptogenic" when the causes leading to this condition cannot be identified.

The determination of its causes plays a pivotal role in the progression of cirrhosis, as therapeutic plans greatly depend on the disease's etiology and many of its complications can be avoided. In the 21st century, given the advanced diagnostic tools and medical progress, the percentage of cryptogenic cirrhosis is substantially smaller: unknown causes are attributed to a 10% of cirrhosis cases, a number greatly diminished in comparison to statistics of the past.

One of the most common causes of cirrhosis is alcoholism. It is indeed an interesting fact that people with cryptogenic cirrhosis exhibit the same degree of fibrosis and scarring as those suffering from an alcoholic cirrhosis, even though they do not consume large amounts of alcohol. During the past years, the suggestion has been made that many cases deemed cryptogenic cirrhosis are actually caused by nonalcoholic steatohepatitis (NASH), a disease which leads to the accumulation of fat in the liver [3]. NASH patients can even be as young as children and do not consume large amounts of alcohol either. Some may not even be recreational drinkers. This disease leads to advanced cirrhosis that produces symptoms only at the progressed stages.

Patient Information

Generally, cirrhosis is a late-stage, untreatable liver disease, with typical structural alterations that involve scarring of the liver, fibrosis and nodules. Cirrhosis can be caused by other conditions, such as hepatitis B or C, alcoholism, obesity, diabetes, Wilson's disease and many more. In some cases, the exact causes having led to cirrhosis cannot be discovered; the condition is therefore termed "cryptogenic cirrhosis".

On many occasions, patients that are thought to have cryptogenic cirrhosis are actually individuals affected by NAFLD, which stands for non-alcoholic fatty liver disease. This condition results in the abnormal accumulation of fat in the liver and its final, most extreme stage is non-alcoholic steatohepatitis (NASH). People with NASH develop cirrhosis, with the same characteristics as people who consume excessive amounts of alcohol, even though the former are not drinkers or consume little amounts of alcohol.

Cryptogenic cirrhosis usually affects people who are older than 60 years, even though it might also be observed in some younger patients, even in children. Symptoms include weakness, abdominal swelling, fever, jaundice and inexplicable weight loss. The treatment of cryptogenic cirrhosis is solely a liver transplant.

References

Article

  1. Anthony PP, Ishah KG, Nayak NC, Pouslen ME, Scheuer PJ, Sorbin LH. The morphology of cirrhosis: definition, nomenclature, and classification. Bulletin of the World Health Organization 1977; 55: 521-40. 2. 
  2. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978 May;31:395-414.
  3. Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA. 2003 Jun 11;289(22):3000-4.
  4. Riley TR, Taheri M, Schreibman IR. Does weight history affect fibrosis in the setting of chronic liver disease?. J Gastrointestin Liver Dis. Sep 2009;18(3):299-302.
  5. Johnson PJ, McFarlane IG. Meeting repor t: International Autoimmune Hepatitis Group. Hepatology 1993 Oct;18:998-1005. 
  6. Alvarez F, Berg PA, Bianchi FB. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999 Nov;31:929-38.
  7. Sherlock S, Dick R, Van Leeuwen DJ. Liver biopsy today. The Royal Free Hospital experience. J Hepatol. 1985;1:75-85.
  8. Tobkes AI, Nord HJ. Liver biopsy: review of methodology and complications. Digestion. 1995 Sep-Oct; 13: 267-74.
  9. Ratziu V, Bugianesi E, Dixon J, et al. Histological progression of non-alcoholic fatty-liver disease: a critical reassessment based on liver sampling variability. Aliment Pharmacol Ther. 2007 Sep; 26: 821-30.
  10. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986 Mar; 1: 523-5. 
  11. Schlichting P, Holund B, Poulsen H. Liver biopsy in chronic aggressive hepatitis. Diagnostic reproducibility in relation to size of specimen. Scand J Gastroenterol. 1983 Jan;18(1):27-32.
  12. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002 Oct;97(10):2614-8.

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Last updated: 2018-06-22 02:16