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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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